Rationale and design of an investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized trial to evaluate the effects of finerenone on vascular stiffness and cardiorenal biomarkers in type 2 diabetes and chronic kidney disease (FIVE-STAR).

BACKGROUND: The overactivation of mineralocorticoid receptor (MR) plays a key pathological role in the progression of cardiovascular and renal diseases by promoting pro-inflammatory and pro-fibrotic signaling. Recently, it has been found that finerenone, a novel nonsteroidal selective MR antagonist, can robustly improve cardiorenal outcomes in patients with type 2 diabetes (T2D) and a wide spectrum of chronic kidney disease (CKD). However, the mechanisms underlying the cardiorenal benefits of finerenone are poorly understood. Further, whether the clinical benefits are mediated by an improvement in vascular stiffness is not confirmed. Therefore, the current study aims to evaluate the effects of finerenone on vascular stiffness as assessed using cardio ankle vascular index (CAVI) and relevant cardiorenal biomarkers in patients with T2D and CKD. METHODS: The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease (FIVE-STAR) is an ongoing, investigator-initiated, multicenter, prospective, placebo-controlled, double-blind, randomized clinical trial in Japan. Its target sample size is 100 subjects. Recruitment will be performed from September 2023 to July 2024. After obtaining informed consent, eligible participants with T2D and CKD (25 mL/min/1.73 m2 ≤ estimated glomerular filtration ratio [eGFR] < 90 mL/min/1.73 m2 and 30 mg/g Cr ≤ urinary albumin-to-creatinine ratio [UACR] < 3500 mg/g Cr) will be equally randomized to receive 24-week treatment with either finerenone (starting dose at 10 mg once daily in participants with a baseline eGFR < 60 mL/min/1.73 m2 or at 20 mg once daily in those with a baseline eGFR ≥ 60 mL/min/1.73 m2) or dose-matched placebo. The primary endpoint is the change from baseline in CAVI at 24 weeks. The secondary endpoints are changes from baseline in UACR at 12 and 24 weeks and relevant serum and urinary biomarkers at 24 weeks. As an exploratory endpoint, proteomic analysis using the Olink® Target 96 panels will be also performed. DISCUSSION: FIVE-STAR is the first trial evaluating the therapeutic impact of finerenone on vascular stiffness and relevant cardiorenal biomarkers in patients with T2D and CKD. This study will provide mechanistic insights on the clinical benefits of finerenone based on recent cardiovascular and renal outcome trials. Trial registration Unique Trial Number, NCT05887817 ( https://clinicaltrials.gov/ct2/show/NCT05887817 ) and jRCTs021230011 ( https://jrct.niph.go.jp/latest-detail/jRCTs021230011 ).

Comparison of phrenic nerve injury and its effect on the extrapulmonary vein structures with cryoballoon and hot-balloon ablation systems: considering the lesion created on the superior vena cava as a surrogate marker.

Preventing phrenic nerve injury (PNI) during balloon-based ablation is essential. The superior vena cava-right atrial (SVC-RA) junction is located just opposite the balloon position during right superior pulmonary vein (RSPV) ablation, and the phrenic nerve runs nearby on the lateral side. We compared the occurrence of PNI between the two balloon-based ablation systems and also the lesions created at the SVC-RA junction, which were expected to represent the effect on extra-PV structures. Cryoballoon ablation (CBA, n = 110) and hot-balloon ablation (HBA, n = 90) were performed in atrial fibrillation patients. High-density maps of the SVC-RA junction were created in 93 patients (CBA = 53, HBA = 40), and the damaged area (< 1.0 mV) was determined as an "SVC lesion". CBA had a higher occurrence of transient PNI (7.3% vs 1.1%, p = 0.035), but all recovered during the 6-month follow-up. An apparent SVC lesion was documented in 43% of the patients (40/93), and all patients with PNI had this lesion. CBA created a frequent (CBA vs HBA = 55% vs 28%, p = 0.008) and wider (0.8[0.4-1.7] cm2 vs 0.5[0.3-0.7] cm2, p = 0.005) SVC lesion than HBA. A multivariate analysis revealed that the use of a CBA system was a predictive factor of the occurrence of SVC lesions. CBA had a higher occurrence of transient PNI but not a permanent form. Every patient with PNI had lesions on the SVC-RA junction, and CBA revealed more substantial ablation effects at the SVC-RA junction than HBA. This may be caused by the different characteristics of the two balloon-based ablation systems and their balloon positions.

Clinical and Angiographic Outcomes of Elective Paclitaxel-Coated Balloon Angioplasty in Comparison with Drug-Eluting Stents for De Novo Coronary Lesions in Large Vessels.

We retrospectively examined the feasibility of paclitaxel-coated balloon (PCB) angioplasty for de novo stenosis in large coronary vessels (LV; pre- or postprocedural reference vessel diameter ≥ 2.75 mm) in comparison with placement of drug-eluting stents (DESs).Consecutive de novo stenotic lesions in the LV electively and successfully treated with either PCB (n = 73) or DESs (n = 81) from January 2016 to December 2018 at our center were included. The primary endpoint was the incidence of target lesion failure (TLF), including cardiac death, nonfatal myocardial infarction, and target vessel revascularization. The impact of PCB on TLF was examined using Cox proportional hazards models by including 39 variables. The secondary endpoint, angiographic restenosis, defined as a follow-up percent diameter stenosis > 50, was examined in angiographic follow-up lesions after PCB angioplasty (n = 56) and DES placement (n = 53). This retrospective investigation was conducted in July 2022.The mean PCB size and length were 3.23 ± 0.42 and 18.4 ± 4.3 mm, respectively. The TLF frequency in the PCB group (6.8% during the mean observational interval of 1536 ± 538 days) was not significantly different from that in the DES group (14.6%, 1344 ± 606 days, P = 0.097). PCB was not a significant predictor of TLF in the univariate analysis (hazard ratio: 0.424; 95%CI: 0.15-1.21; P = 0.108). There was no angiographic restenosis after PCB angioplasty.The present observational single-center study showed that PCB for de novo stenosis in the LV had no significant adverse impact on TLF and had favorable angiographic outcomes.

Optimal target of LDL cholesterol level for statin treatment: challenges to monotonic relationship with cardiovascular events.

BACKGROUND: Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the "The lower is the better" concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a "threshold" value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. METHODS: For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the "threshold" value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C - threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. RESULTS: For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01-1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. CONCLUSIONS: Our analysis model suggests that a "threshold" value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov . Unique identifier: NCT01042730.

Association between serum insulin levels and heart failure-related parameters in patients with type 2 diabetes and heart failure treated with canagliflozin: a post-hoc analysis of the randomized CANDLE trial.

BACKGROUND: Insulin resistance and hyperinsulinemia in patients with type 2 diabetes (T2D) are adversely associated with the development and worsening of heart failure (HF). Herein, we sought to investigate the effect of canagliflozin on insulin concentrations and the associations of changes in insulin concentrations with HF-related clinical parameters in patients with T2D and HF. METHODS: This was a post-hoc analysis of the investigator-initiated, multicenter, open-label, randomized, controlled CANDLE trial for patients with T2D and chronic HF (UMIN000017669). The endpoints were the effects of 24 weeks of canagliflozin treatment, relative to glimepiride treatment, on insulin concentrations and the relationship between changes in insulin concentrations and clinical parameters of interest, including New York Heart Association (NYHA) classification. The effects of canagliflozin on those parameters were also analyzed by baseline insulin level. RESULTS: Among the participants in the CANDLE trial, a total of 129 patients (canagliflozin, n = 64; glimepiride, n = 65) who were non-insulin users with available serum insulin data both at baseline and week 24 were included in this analysis. Overall, the mean age was 69.0 ± 9.4 years; 75% were male; the mean HbA1c was 6.8 ± 0.7%; and the mean left ventricular ejection fraction was 59.0 ± 14.1%, with parameters roughly balanced between treatment groups. Canagliflozin treatment significantly reduced insulin concentrations at week 24 (p < 0.001), and the between-group difference (canagliflozin minus glimepiride) in those changes was - 3.52 mU/L (95% confidence interval, - 4.85 to - 2.19; p < 0.001). Decreases in insulin concentrations, irrespective of baseline insulin level, were significantly associated with improvement in NYHA class in patients treated with canagliflozin. CONCLUSION: Our findings suggest that canagliflozin treatment in patients with T2D and HF ameliorated excess insulin overload, contributing to the improvement of clinical HF status. TRIAL REGISTRATION: University Medical Information Network Clinical Trial Registry, number 000017669, Registered on May 25, 2015.

A Propensity Score-Matched Comparison of Midterm Outcomes Between Drug-Coated Balloons and Drug-Eluting Stents for Patients with Acute Coronary Syndrome.

We conducted a single-center, retrospective, lesion-based study to examine the safety and efficacy of drug-coated balloons (DCBs) for de novo coronary stenosis in patients with acute coronary syndrome (ACS) by comparing them with those of drug-eluting stents (DESs).A total of 309 consecutive lesions in patients with ACS who were successfully treated by emergent procedures using either a DCB (n = 107) or a DES between January 2016 and December 2019 were included in the study. The primary endpoint was the incidence of target lesion failure (TLF), defined as cardiac death without mortality due to ACS, non-fatal myocardial infarction, and any target lesion revascularization, including acute occlusion, after DCB use and definite stent thrombosis after DES placement. A propensity score-matched analysis was used to adjust the 36 baseline variables. Retrospective investigations were conducted in January 2021.Baseline adjustment yielded 91 lesions in each group, with a mean balloon size of 3.02 ± 0.22 mm and a mean length of 20.9 ± 6.2 mm in the DCB group. The frequency of TLF in the DCB group (9.9% during the mean observational interval of 671 ± 508 days) was not significantly different from that in the DES group (13.2% during a period of 626 ± 543 days, P = 0.467). The cumulative TLF-free ratio in the DCB group was not significantly different from that in the DES group (P = 0.475, log-rank test).The present propensity score-matched comparison showed statistically equivalent midterm clinical outcomes after DCB use to those of DES placement for de novo lesions in patients with ACS treated by emergent procedures.

[Two Cases of Unilateral Multifocal Renal Cell Carcinoma Treated with Robot-Assisted Partial Nephrectomy].

Recently, robot-assisted laparoscopic partial nephrectomy (RAPN) has become a commonly performed surgical treatment for small renal tumors, but for difficult cases, such as those presenting with multiple tumors, there are few institutions with experience. We herein report two cases of unilateral multifocal renal cell carcinoma that were successfully treated with RAPN. Case 1: A 65-year-oldwoman was incidentally identified to have two right kidney tumors on imaging. RAPN under cold ischemia was performed. Pathological examinations revealed both tumors to be clear cell carcinoma. Case 2: A 56-year-oldman was incidentally found to have two left kidney tumors on imaging. RAPN under zero-ischemia and warm ischemia was performed. Pathological examinations revealed both tumors to be clear cell carcinoma. In both cases, no recurrence has been observed, and the decrease that occurred in the renal function was mild during the one-and-a half year follow-up.

[Treatment of Parastomal Hernia Following Robot-Assisted Radical Cystectomy and Cutaneous Ureterostomy : A Case Report].

The patient was an 82-year-old woman with localized muscle-invasive bladder cancer, who underwent robot-assisted radical cystectomy and cutaneous ureterostomy. On the 3rd day after the operation, she suddenly complained of abdominal pain. Abdominal computed tomographic scans revealed parastomal hernia. The patient underwent manual reduction of hernia, but had repeated recurrences of parastomal hernia within a few days. On the 14th day we performed a laparoscopic hernia repair. Observation of the stoma site revealed a laceration of the peritoneum and fascia, and the small intestine was prolapsed. We pulled the small intestine out and ligated the laceration with Mediflex® Suture Grasper Closure Device. After re-operation, there was no recurrence of bladder cancer and parastomal hernia, and the stoma appliances could be put on without any trouble.

Cryofreezing for slow-pathway modification in patients with slow-fast AVNRT: Efficacy, safety, and electroanatomical relation between sites of transient AV block and sites of successful cryoablation.

INTRODUCTION: Cryoablation has emerged as an alternative to radiofrequency ablation for treating atrioventricular nodal reentrant tachycardia (AVNRT). The aim of this prospective study was to evaluate the efficacy and safety of cryoapplication at sites within the mid/high septal region of Koch's triangle and the relation between sites of transient AV block (AVB) and sites of successful cryoablation. METHODS AND RESULTS: Included were 45 consecutive patients undergoing slow-fast AVNRT cryoablation. Initial delivery of cryoenergy was to the mid-septal to high septal region of Koch's triangle. Transient AVB occurred during cryoenergy delivery in 62% (28/45) of patients. Median distance between sites at which cryofreezing successfully eliminated slow pathway conduction and sites of AVB was 4.0 (3.25-5.0) mm. Sites of successful cryoablation tended to be to the left and inferior to the AVB sites. The atrial/ventricular electrogram ratio was significantly lower at sites of successful cryoablation than at AVB sites (0.25 [0.17-0.56] vs. 0.80 [0.36-1.25], p < .001). Delayed discrete or fractionated atrial electrograms were recorded more frequently at sites of successful cryoablation than at AVB sites (78% vs. 20%, p < .001). No persistent AV conduction disturbance occurred, and 96% (43/45) of patients showed absence of recurrence at a median follow-up time of 25.0 months. CONCLUSION: Cryoablation of slow-fast AVNRT and targeting the mid/high septal region of Koch's triangle was highly successful. AVB frequently emerged near the site at which the slow pathway was eliminated but always resolved by regulating the energy delivery under careful monitoring, and it may be distinguishable by its local electrogram features.

A porcine study of the area of heated tissue during hot-balloon ablation: Implications for the clinical efficacy and safety.

INTRODUCTION: Hot-balloon ablation depends solely on thermal conduction, and myocardial tissue is ablated by only conductive heating from the balloon surface. Despite growing clinical evidence of the efficacy and safety of hot-balloon ablation for atrial fibrillation (AF), the actual tissue temperature and the mechanism of heating during such ablation has not been clarified. To determine, by means of a porcine study, the temperatures of tissues targeted during hot-balloon ablation of AF performed with hot-balloon set temperatures of 73°C or 70°C, in accordance with the temperatures now used clinically. METHODS: After a right thoracotomy, thermocouples with markers were implanted epicardially on the superior vena cava (SVC) and pulmonary veins (PVs) in six pigs. The tissue temperatures during hot-balloon ablation (balloon set temperatures of 73°C and 70°C, 180 s/PV) were recorded, and the maximum tissue temperatures and fluoroscopically measured distance from the balloon surface to the target tissues were assessed. RESULTS: Sixteen SVC- and 18 PV-targeted energy deliveries were performed. Full-thickness circumferential PV lesions were created with all hot-balloon applications. A significant inverse relation was found between the recorded tissue temperatures and distance (r = -.67; p < .001) from the balloon surface. No tissue temperature exceeded either of the balloon set temperatures. The best distance cutoff value for achieving lethal tissue temperatures more than 50°C was 3.6 mm. CONCLUSION: The hot-balloon set temperature, energy delivery time, and tissue temperature data obtained in this porcine study supported the clinical efficacy and safety of the hot-balloon ablation as currently practiced in patients with AF.

Utility of hot-balloon-based pulmonary vein isolation under balloon surface temperature monitoring: First clinical experience.

INTRODUCTION: A new hot balloon system that registers balloon surface temperature (BST) during energy delivery is now available for clinical use in Japan. This study sought to investigate the utility of BST measurement for achievement of pulmonary vein isolation (PVI) by a single-shot energy delivery strategy during hot balloon ablation (HBA). METHODS: We applied and tested the system in 30 consecutive patients undergoing HBA for paroxysmal or early-persistent atrial fibrillation (AF). We also performed real-time PV potential monitoring using a circular catheter. RESULTS: Acute PVI was achieved with single hot balloon shots in 88% (106/120) of the PVs. Real-time BSTs and PV potentials were recorded in all cases. Mean BST at documentation of PVI was 49.4°C, and acute reconnections were observed in most cases (86%, 12/14) in which the single-shot technique was ineffective. Time-to-isolation (TTI) (23.1 ± 8.7 s vs. 36.3 ± 9.3 s, p < .01) and median BST (59.9 ± 2.6°C vs. 55.7 ± 1.9°C, p < .01) differed significantly between cases in which PVI was achieved (vs. those in which PVI was not achieved). Multivariable analysis revealed strong association between both TTI and median BST and acute PVI. The best median BST cutoff value for achieving PVI with a single shot was >58.7°C (sensitivity 67.0%, specificity 100%). CONCLUSION: Our data suggest that real-time BST monitoring during energy applications is useful for predicting achievement of acute PVI by a single shot during HBA.

Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial.

BACKGROUNDS/AIM: Sodium glucose co-transporter 2 inhibitors promote osmotic/natriuretic diuresis and reduce excess fluid volume, and this improves cardiovascular outcomes, including hospitalization for heart failure. We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD). METHODS: The study was a post-hoc analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24 weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10 mg once daily, n = 52) and placebo (n = 53) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24 weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration. RESULTS: In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by - 2.23% (95% CI - 5.72 to 1.25) at week 4, - 8.07% (- 12.76 to - 3.37) at week 12, and - 5.60% (- 9.87 to - 1.32) at week 24; eEV by - 70.3 mL (95% CI - 136.8 to - 3.8) at week 4, - 135.9 mL (- 209.6 to - 62.3) at week 12, and - 144.4 mL (- 226.3 to - 62.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r = 0.351, p = 0.015), but not with change in eEV. CONCLUSIONS: Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24 weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

Comparison of the clinical effect of empagliflozin on glycemic and non-glycemic parameters in Japanese patients with type 2 diabetes and cardiovascular disease treated with or without baseline metformin.

BACKGROUND: The most recent treatment guidelines for type 2 diabetes (T2D) recommend sodium-glucose cotransporter 2 (SGLT2) inhibitors should be considered preferentially in patients with T2D with either a high cardiovascular risk or with cardiovascular disease (CVD), regardless of their diabetes status and prior use of conventional metformin therapy. Whether the therapeutic impact of SGLT2 inhibitors on clinical parameters differs according to the use of metformin therapy however remains unclear. METHODS: The study was a post hoc analysis of the EMBLEM trial (UMIN000024502). All participants (n = 105; women 31.4%; mean age 64.8 years) had both T2D and CVD and were randomized to either 24 weeks of empagliflozin 10 mg daily or placebo. Analysis of the data assessed the effect of empagliflozin on changes from baseline to 24 weeks in glycemic and non-glycemic clinical parameters, according to the baseline use of metformin. RESULTS: Overall, 53 (50.5%) patients received baseline metformin. In the 52 patients treated with empagliflozin (48.1% with baseline metformin), the decrease in systolic blood pressure from baseline levels was greater in patients receiving metformin, compared to that observed in metformin-naïve patients (group difference - 8.5 [95% confidence interval (CI) - 17.7 to 0.6 mmHg], p = 0.066). Reduction in body mass index (BMI) was significantly greater in patients receiving baseline metformin, relative to nonusers (- 0.54 [95% CI - 1.07 to - 0.01] kg/m2, p = 0.047). The group ratio (baseline metformin users vs. nonusers) of proportional changes in the geometric mean of high-sensitivity Troponin-I (hs-TnI) was 0.74 (95% CI 0.59 to 0.92, p = 0.009). No obvious differences were observed in glycemic parameters (fasting plasma glucose, glycohemoglobin, and glycoalbumin) between the baseline metformin users and nonusers. CONCLUSION: Our findings suggest 24 weeks of empagliflozin treatment was associated with an improvement in glycemic control, irrespective of the baseline use of metformin therapy. The effects of empagliflozin on reductions in BMI and hs-TnI were more apparent in patients who received baseline metformin therapy, compared to that observed in metformin-naïve patients. Trial registration University Medical Information Network Clinical Trial Registry, number 000024502.

[A Case of Metachronous Quintuple Cancer Involving the Stomach, Rectum, Colon, Liver and Prostate].

Advances and improvements in cancer diagnosis and treatment have made it possible to find multiple primary cancers. We report here a rare case of metachronous quintuple cancer involving the stomach, rectum, colon, liver and prostate. An 80s‒ year‒old male was referred to our hospital with abnormality on upper GI series. He had undergone a distal gastrectomy in May 2005. Postoperative diagnosis was advanced gastric cancer (pT2N1M0, pStage ⅡA). In August 2006, anterior resection was performed with a diagnosis of advanced rectal cancer(pT3N0M0, pStage Ⅱa). For ascending colon polyps, endoscopic submucosal dissection was performed with a diagnosis of adenocarcinoma in adenoma(pTisN0M0, pStage 0)in September 2007. In June 2016, laparoscopic ileocecal resection was performed with a diagnosis of advanced cecum cancer(pT3N0M0, pStage Ⅱa). Follow up CT images showed a liver tumor in S4. Partial liver resection was performed in October 2010. Postoperative pathological diagnosis was hepatocellular carcinoma(pT2N0M0, pStage Ⅱ). Prostate cancer(cT2aN0M0)was treated by androgen deprivation therapy from February 2018. Although he had high‒frequency microsatellite instability, germline mutations in hMLH1 and hMSH2 genes were not detected. Histopathological examination showed that each tumor was an independent tumor and had not metastasized from any others. The patient had a good clinical course after these treatment until now.

Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial.

BACKGROUND: An elevated level of serum uric acid (SUA) is associated with an increased risk of cardiovascular disease. Pharmacological intervention with urate-lowering agents, such as the conventional purine analogue xanthine oxidase (XO) inhibitor, allopurinol, has been used widely for a long period of time in clinical practice to reduce SUA levels. Febuxostat, a novel non-purine selective inhibitor of XO, has higher potency for inhibition of XO activity and greater urate-lowering efficacy than conventional allopurinol. However, clinical evidence regarding the effects of febuxostat on atherosclerosis is lacking. The purpose of the study was to test whether treatment with febuxostat delays carotid intima-media thickness (IMT) progression in patients with asymptomatic hyperuricemia. METHODS AND FINDINGS: The study was a multicenter, prospective, randomized, open-label, blinded-endpoint clinical trial undertaken at 48 sites throughout Japan between May 2014 and August 2018. Adults with both asymptomatic hyperuricemia (SUA >7.0 mg/dL) and maximum IMT of the common carotid artery (CCA) ≥1.1 mm at screening were allocated equally using a central web system to receive either dose-titrated febuxostat (10-60 mg daily) or as a control-arm, non-pharmacological lifestyle modification for hyperuricemia, such as a healthy diet and exercise therapy. Of the 514 enrolled participants, 31 were excluded from the analysis, with the remaining 483 people (mean age 69.1 years [standard deviation 10.4 years], female 19.7%) included in the primary analysis (febuxostat group, 239; control group, 244), based on a modified intention-to-treat principal. The carotid IMT images were recorded by a single sonographer at each site and read in a treatment-blinded manner by a single analyzer at a central core laboratory. The primary endpoint was the percentage change from baseline to 24 months in mean IMT of the CCA, determined by analysis of covariance using the allocation adjustment factors (age, gender, history of type 2 diabetes, baseline SUA, and baseline maximum IMT of the CCA) as the covariates. Key secondary endpoints included changes in other carotid ultrasonographic parameters and SUA and the incidence of clinical events. The mean values (± standard deviation) of CCA-IMT were 0.825 mm ± 0.173 mm in the febuxostat group and 0.832 mm ± 0.175 mm in the control group (mean between-group difference [febuxostat - control], -0.007 mm [95% confidence interval (CI) -0.039 mm to 0.024 mm; P = 0.65]) at baseline; 0.832 mm ± 0.182 mm in the febuxostat group and 0.848 mm ± 0.176 mm in the control group (mean between-group difference, -0.016 mm [95% CI -0.051 mm to 0.019 mm; P = 0.37]) at 24 months. Compared with the control group, febuxostat had no significant effect on the primary endpoint (mean percentage change 1.2% [95% CI -0.6% to 3.0%] in the febuxostat group (n = 207) versus 1.4% [95% CI -0.5% to 3.3%] in the control group (n = 193); mean between-group difference, -0.2% [95% CI -2.3% to 1.9%; P = 0.83]). Febuxostat also had no effect on the other carotid ultrasonographic parameters. The mean baseline values of SUA were comparable between the two groups (febuxostat, 7.76 mg/dL ± 0.98 mg/dL versus control, 7.73 mg/dL ± 1.04 mg/dL; mean between-group difference, 0.03 mg/dL [95% CI -0.15 mg/dL to 0.21 mg/dL; P = 0.75]). The mean value of SUA at 24 months was significantly lower in the febuxostat group than in the control group (febuxostat, 4.66 mg/dL ± 1.27 mg/dL versus control, 7.28 mg/dL ± 1.27 mg/dL; mean between-group difference, -2.62 mg/dL [95% CI -2.86 mg/dL to -2.38 mg/dL; P < 0.001]). Episodes of gout arthritis occurred only in the control group (4 patients [1.6%]). There were three deaths in the febuxostat group and seven in the control group during follow-up. A limitation of the study was the study design, as it was not a placebo-controlled trial, had a relatively small sample size and a short intervention period, and only enrolled Japanese patients with asymptomatic hyperuricemia. CONCLUSIONS: In Japanese patients with asymptomatic hyperuricemia, 24 months of febuxostat treatment did not delay carotid atherosclerosis progression, compared with non-pharmacological care. These findings do not support the use of febuxostat for delaying carotid atherosclerosis in this population. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trial Registry UMIN000012911.

Hot balloon versus cryoballoon ablation for persistent atrial fibrillation: Lesion area, efficacy, and safety.

INTRODUCTION: The clinical efficacy and safety of hot balloon ablation (HBA) for the treatment of persistent AF (PerAF) remain unclear. We aimed to evaluate the clinical efficacy and safety of HBA versus cryoballoon ablation (CBA) as a treatment for PerAF. METHODS: Of 195 consecutive patients who underwent initial catheter ablation for PerAF (AF lasting for longer than 7 days but shorter than 12 months), 158 propensity score-matched (79 HBA and 79 CBA) patients were included in our retrospective study. All patients who underwent HBA received applications of energy to the upper posterior LA wall with a larger balloon in addition to single shots to each pulmonary vein (PV) ostium, whereas those who underwent CBA received simple single-shot applications. The electrically isolated surface area (ISA), including the PV antrum and part of the posterior LA wall, was assessed by high-resolution mapping. RESULTS: The success of the PV isolation with balloon shots alone did not differ between HBA and CBA (81% vs. 85%; p = .52). The ISA was generally wide in both groups and significantly larger in the HBA group than in the CBA group (61 ± 16% vs. 51 ± 12%; p < .001). The incidence of procedure-related complications did not differ significantly (HBA 4% vs. CBA 1%; p = .62) nor did the arrhythmia recurrence rate (HBA 11% vs. CBA 18% at 18 months; p = .26). CONCLUSION: Despite the difference in protocols, HBA and CBA performed for PerAF appear comparable in terms of wide antral lesion creation, clinical efficacy, and safety. Further prospective studies, based on a unified methodology, are needed.

A multicenter study on the clinical characteristics and risk factors of in-hospital mortality in patients with mechanical complications following acute myocardial infarction.

Mechanical complications (MCs) following acute myocardial infarction (AMI), such as ventricular septal rupture (VSR), free-wall rupture (FWR), and papillary muscle rupture (PMR), are fatal. However, the risk factors of in-hospital mortality among patients with MCs have not been previously reported in Japan. The purpose of this study was to evaluate the prognostic factors of in-hospital mortality in these patients. The study cohort consisted of 233 consecutive patients with MCs from the registry of 10 facilities in the Cardiovascular Research Consortium-8 Universities (CIRC-8U) in East Japan between 1997 and 2014 (2.3% of 10,278 AMI patients). The authors conducted a retrospective observational study to analyse the correlation between the subtypes of MCs with in-hospital mortality, clinical data, and medical treatment. We observed a decreasing incidence of MC (1997-2004: 3.7%, 2005-2010: 2.1%, 2011-2014: 1.9%, p < 0.001). In-hospital mortality among patients with MCs was 46%. Thirty-three percent of patients with MCs were not able to undergo surgical repair due to advanced age or severe cardiogenic shock. In-hospital mortality among patients who had undergone surgical repair was 29% (VSR: 21%, FWR: 33%, PMR: 60%). In patients with MCs, hazard ratio for in-hospital mortality according to multivariate analysis of without surgical repair was 5.63 (95% CI 3.54-8.95). In patients with surgical repair, the hazard ratios of blow-out-type FWR (5.53, 95% confidence interval (CI) 2.22-13.76), those with renal dysfunction (3.11, 95% CI 1.37-7.05), and those receiving venoarterial extracorporeal membrane oxygenation (VA-ECMO) (3.79, 95% CI 1.81-7.96) were significantly high. Although primary percutaneous coronary intervention (PCI) is associated with decreased incidence of MCs, high in-hospital mortality persisted in patients with MCs that also presented with renal dysfunction and in those requiring VA-ECMO. Early detection and surgical repair of MCs are essential.

High-Dose Versus Low-Dose Pitavastatin in Japanese Patients With Stable Coronary Artery Disease (REAL-CAD): A Randomized Superiority Trial.

BACKGROUND: Current guidelines call for high-intensity statin therapy in patients with cardiovascular disease on the basis of several previous "more versus less statins" trials. However, no clear evidence for more versus less statins has been established in an Asian population. METHODS: In this prospective, multicenter, randomized, open-label, blinded end point study, 13 054 Japanese patients with stable coronary artery disease who achieved low-density lipoprotein cholesterol (LDL-C) <120 mg/dL during a run-in period (pitavastatin 1 mg/d) were randomized in a 1-to-1 fashion to high-dose (pitavastatin 4 mg/d; n=6526) or low-dose (pitavastatin 1 mg/d; n=6528) statin therapy. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke, or unstable angina requiring emergency hospitalization. The secondary composite end point was a composite of the primary end point and clinically indicated coronary revascularization excluding target-lesion revascularization at sites of prior percutaneous coronary intervention. RESULTS: The mean age of the study population was 68 years, and 83% were male. The mean LDL-C level before enrollment was 93 mg/dL with 91% of patients taking statins. The baseline LDL-C level after the run-in period on pitavastatin 1 mg/d was 87.7 and 88.1 mg/dL in the high-dose and low-dose groups, respectively. During the entire course of follow-up, LDL-C in the high-dose group was lower by 14.7 mg/dL than in the low-dose group (P<0.001). With a median follow-up of 3.9 years, high-dose as compared with low-dose pitavastatin significantly reduced the risk of the primary end point (266 patients [4.3%] and 334 patients [5.4%]; hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; P=0.01) and the risk of the secondary composite end point (489 patients [7.9%] and 600 patients [9.7%]; hazard ratio, 0.83; 95% confidence interval, 0.73-0.93; P=0.002). High-dose pitavastatin also significantly reduced the risks of several other secondary end points such as all-cause death, myocardial infarction, and clinically indicated coronary revascularization. The results for the primary and the secondary composite end points were consistent across several prespecified subgroups, including the low (<95 mg/dL) baseline LDL-C subgroup. Serious adverse event rates were low in both groups. CONCLUSIONS: High-dose (4 mg/d) compared with low-dose (1 mg/d) pitavastatin therapy significantly reduced cardiovascular events in Japanese patients with stable coronary artery disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01042730.

Characterization of Residual Conduction Gaps After HotBalloon-Based Antral Ablation of Atrial Fibrillation　- Evidence From Ultra-High-Resolution 3-Dimensional Mapping.

BACKGROUND: The electrophysiological characteristics of residual conduction gaps between the left atrium (LA) and pulmonary veins (PVs) after HotBalloon-based wide antral ablation (HBWA) of atrial fibrillation (AF) remain incompletely understood. This study aimed to characterize the residual gaps by means of ultra-high-resolution mapping.Methods and Results:A total of 55 AF patients underwent HBWA by a predetermined protocol (6-shot total-based antral approach). LA-PV maps were created using 64-electrode minibasket catheters. In total, 55 residual gaps were identified among 26 (47%) patients. Residual gaps included 33 left superior (LS: 60%), 10 left inferior (18%), 6 right superior (11%), and 6 right inferior (11%) PVs. Those gaps demonstrated both extremely lower bipolar amplitudes (0.11 [interquartile range: 0.06-0.27] mV) and conduction velocities (0.75±0.27 m/s); however, the length was confined (10.3±4.1 mm) except for the LSPV anterior carina (12.2±2.4 mm) region. Among the carina regions, all gaps had far-field potentials consistently added to the PV potentials. Left atrial appendage pacing to split the far-field activity identified confined gap regions (6.7±1.9 mm). Touch-up ablation eliminated the residual PV potentials in all cases. CONCLUSIONS: HBWA resulted in a certain degree of residual gap conduction in particular antral regions. These gaps exhibited narrow lengths with lower amplitudes, and often had far-field recordings from the left atrial appendage. Combined with pacing maneuvers, ultra-high-resolution activation maps could both visualize all confined gaps and ensure a bare minimum of touch-up ablations in all patients with gap conduction.

[A Case of IgG4-Related Disease Diagnosed by Prostate Biopsy].

A 74 year-old man presented with complaints of dysuria and miction pain. Since the prostate volume was 43.5 ml, the patient was scheduled for surgical treatment of benign prostatic hyperplasia. However, prostate cancer was suspected from the magnetic resonance imaging findings and a prostate biopsy was performed. No malignant findings were observed in the pathological results, but numerous plasma cells stained positive for IgG4. Abdominal computed tomography showed pancreatic head enlargement with surrounding inflammatory changes and elevated serum IgG4 was also observed. The patient was diagnosed with IgG4-related disease (pancreatitis/prostatitis). Dysuria improved with induction of 30 mg prednisolone. The patient no longer needed to take the α1 blocker and 5α reductase inhibitor. The international prostate symptom score and urine flow measurement indicated that the patient remained in good condition at 18 months since the start of treatment.