Rubicon prevents autophagic degradation of GATA4 to promote Sertoli cell function.

Autophagy degrades unnecessary proteins or damaged organelles to maintain cellular function. Therefore, autophagy has a preventive role against various diseases including hepatic disorders, neurodegenerative diseases, and cancer. Although autophagy in germ cells or Sertoli cells is known to be required for spermatogenesis and male fertility, it remains poorly understood how autophagy participates in spermatogenesis. We found that systemic knockout mice of Rubicon, a negative regulator of autophagy, exhibited a substantial reduction in testicular weight, spermatogenesis, and male fertility, associated with upregulation of autophagy. Rubicon-null mice also had lower levels of mRNAs of Sertoli cell-related genes in testis. Importantly, Rubicon knockout in Sertoli cells, but not in germ cells, caused a defect in spermatogenesis and germline stem cell maintenance in mice, indicating a critical role of Rubicon in Sertoli cells. In mechanistic terms, genetic loss of Rubicon promoted autophagic degradation of GATA4, a transcription factor that is essential for Sertoli cell function. Furthermore, androgen antagonists caused a significant decrease in the levels of Rubicon and GATA4 in testis, accompanied by elevated autophagy. Collectively, we propose that Rubicon promotes Sertoli cell function by preventing autophagic degradation of GATA4, and that this mechanism could be regulated by androgens.

Comparison of myocardial injury and inflammation after pulmonary vein isolation for paroxysmal atrial fibrillation between radiofrequency catheter ablation and cryoballoon ablation.

BACKGROUNDS: Several studies have shown the serum high sensitive cardiac troponin I (hs-TnI) a biomarker of myocardium injury, and C-reactive protein (CRP), a biomarker of inflammation, are associated with worse cardiovascular outcomes. We evaluated the relationship between the hs-TnI level in patients with paroxysmal atrial fibrillation (PAF) after pulmonary vein isolation (PVI) and atrial fibrillation (AF) recurrence. METHODS AND RESULTS: We enrolled 263 consecutive PAF patients who underwent PVI from May 2017 to April 2018. We investigated the difference in the relationship between the myocardial injury marker (serum hs-TnI), inflammatory marker (CRP, white blood cell) at 36 to 48 hours after the PVI, and early or late recurrence of AF (ERAF; <3 months and LRAF; from 3 months to 1 year) between the radiofrequency ablation group (R group) and cryoballoon ablation group (C group). The R group consisted of 147 patients and the C groups consisted of 116 patients. The serum hs-TnI level in R group was significantly lower than in the C group (2.33 vs 5.08 ng/mL; P < .001), while the CRP was significantly higher in the R group than C group (2.02 vs 1.10 mg/dL; P < .001). The incidences of an ERAF/LRAF were similar between the two groups. CONCLUSION: Cryoballoon ablation may cause more myocardial injury than radiofrequency catheter ablation, on the contrary, radiofrequency catheter ablation, may cause more inflammation than cryoballoon ablation. However, these phenomena may not affect the recurrence of AF after the PVI in patient with PAF.

Clinical experience of uninterrupted oral anticoagulants during atrial fibrillation ablation in elderly patients: a comparison with non-elderly patients.

It is unclear whether uninterrupted oral anticoagulants (OACs) are acceptable in elderly patients as compared to non-elderly patients. This study aimed to assess the clinical impact of an uninterrupted OAC strategy during atrial fibrillation (AF) ablation in elderly patients. We enrolled 439 consecutive patients who underwent AF ablation with an uninterrupted OAC strategy at our institute. The incidence of bleeding and thromboembolic complications during the AF ablation or within 4 weeks after and the anticoagulation status during the AF ablation were compared between the elderly (age ≧ 75, n = 144) and non-elderly groups (n = 295). There were 22 bleeding complications in the elderly group and 31 in the non-elderly group (15% vs. 11%, p = 0.162) and 3 major bleeding complications in the elderly group and 2 in the non-elderly group (2% vs. 0.7%, p = 0.336). Thromboembolic events were observed in 1 patient in the elderly group and 2 in the non-elderly group (0.7% vs. 0.7%, p = 1.000). The ACT at the end of the procedure was longer in the elderly group than in the non-elderly group (350 s vs. 341 s, p = 0.007) and the proportion of a prolonged ACT of > 400 s (27% vs. 18%, p = 0.046) was more frequent in the elderly group than non-elderly group. A propensity score matched population excluding the age and body weight, revealed that the anticoagulation status during AF ablation was comparable between the two groups. Thus, in the patients undergoing AF ablation with uninterrupted OAC strategy, bleeding complications in elderly patients were similar to those in non-elderly patients. The anticoagulation status during the procedure in elderly patients was more prolonged than that in non-elderly patients.

A case of a "pseudo jump-up phenomenon" caused by retrograde ventricular-His prolongation.

A 35-year-old woman was referred for treatment of a supraventricular tachycardia. The tachycardia was diagnosed as a slow-fast form of atrioventricular nodal reentrant tachycardia. Radiofrequency ablation targeting the antegrade slow pathway was performed at the posterior septum of the right atrium. After the radiofrequency ablation, ventricular extrastimulus pacing was performed to assess the retrograde slow pathway, which was suggested before the ablation. The prolongation of the VA interval with a 10 ms decrease in the S2 pacing interval was 60 ms and retrograde dual pathways were suspected. However, the HA interval did not change and a prolongation of the VA interval was caused by the prolongation of the VH interval and no additional ablation was required.

The Rubicon-WIPI axis regulates exosome biogenesis during ageing.

Cells release intraluminal vesicles in multivesicular bodies as exosomes to communicate with other cells. Although recent studies suggest an intimate link between exosome biogenesis and autophagy, the detailed mechanism is not fully understood. Here we employed comprehensive RNA interference screening for autophagy-related factors and discovered that Rubicon, a negative regulator of autophagy, is essential for exosome release. Rubicon recruits WIPI2d to endosomes to promote exosome biogenesis. Interactome analysis of WIPI2d identified the ESCRT components that are required for intraluminal vesicle formation. Notably, we found that Rubicon is required for an age-dependent increase of exosome release in mice. In addition, small RNA sequencing of serum exosomes revealed that Rubicon determines the fate of exosomal microRNAs associated with cellular senescence and longevity pathways. Taken together, our current results suggest that the Rubicon-WIPI axis functions as a key regulator of exosome biogenesis and is responsible for age-dependent changes in exosome quantity and quality.

Loss of RUBCN/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response.

Upon fasting, adipocytes release their lipids that accumulate in the liver, thus promoting hepatic steatosis and ketone body production. However, the mechanisms underlying this process are not fully understood. In this study, we found that fasting caused a substantial decrease in the adipose levels of RUBCN/rubicon, a negative regulator of macroautophagy/autophagy, along with an increase in autophagy. Adipose-specific rubcn-knockout mice exhibited systemic fat loss that was not accelerated by fasting. Genetic inhibition of autophagy in adipocytes in fasted mice led to a reduction in fat loss, hepatic steatosis, and ketonemia. In terms of mechanism, autophagy decreased the levels of its substrates NCOA1/SRC-1 and NCOA2/TIF2, which are also coactivators of PPARG/PPARγ, leading to a fasting-induced reduction in the mRNA levels of adipogenic genes in adipocytes. Furthermore, RUBCN in adipocytes was degraded through the autophagy pathway, suggesting that autophagic degradation of RUBCN serves as a feedforward system for autophagy induction during fasting. Collectively, we propose that loss of adipose RUBCN promotes a metabolic response to fasting via increasing autophagic activity.

Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis.

Accumulation of senescent cells affects organismal aging and the prevalence of age-associated disease. Emerging evidence suggests that activation of autophagy protects against age-associated diseases and promotes longevity, but the roles and regulatory mechanisms of autophagy in cellular senescence are not well understood. Here, we identify the transcription factor, MondoA, as a regulator of cellular senescence, autophagy, and mitochondrial homeostasis. MondoA protects against cellular senescence by activating autophagy partly through the suppression of an autophagy-negative regulator, Rubicon. In addition, we identify peroxiredoxin 3 (Prdx3) as another downstream regulator of MondoA essential for mitochondrial homeostasis and autophagy. Rubicon and Prdx3 work independently to regulate senescence. Furthermore, we find that MondoA knockout mice have exacerbated senescence during ischemic acute kidney injury (AKI), and a decrease of MondoA in the nucleus is correlated with human aging and ischemic AKI. Our results suggest that decline of MondoA worsens senescence and age-associated disease.

Maximum calcium thickness is a useful predictor for acceptable stent expansion in moderate calcified lesions.

Contemporary debulking devices such as rotational or orbital atherectomy can modify severe calcified lesions before stent implantation. Actually, we occasionally experience stent underexpansion without debulking devices in not severe but moderate calcified lesions although we expect good stent expansion. We aimed to investigate useful calcium parameters correlated with stent expansion in moderate calcified lesions. We enrolled 50 consecutive moderate calcified lesions in 47 patients who underwent optical coherence tomography (OCT) guided percutaneous coronary intervention (PCI) between January 2017 and March 2019. The exclusion criteria were the lesions without any calcium and treated with rotational or orbital atherectomy. We compared stent sizing, length, post balloon sizing, post balloon pressure, mean reference area, pre-procedure area stenosis and various calcium parameters including calcium arc, maximum calcium thickness, depth, longitudinal length in pre-PCI OCT with post-PCI stent expansion by simple and multiple regression analysis. Maximum calcium thickness was an independent predictor for stent expansion, while the other calcium parameters were not associated. The optimal thresholds of maximum calcium thickness for predicting acceptable stent expansion defined by 80% was 880 µm (area under curve: 0.73). Maximum calcium thickness < 880 µm is a useful predictor for acceptable stent expansion in moderate calcified lesions.

Serial angioscopic evaluation of self-expanding stent graft implantation in superficial femoral artery.

We evaluated Viabahn stent-graft (W.L. Gore & Associates, Flagstaff, AZ, USA) implanted in the superficial femoral artery at 6 months and one year after implantation because the patient felt claudication due to repeated restenosis of bare nitinol stent which was implanted just proximal to the site of Viabahn stent-graft. At 6 months, angioscopy showed severe thrombosis in the stent-graft while the stent-graft was entirely patent. However, at one year, angioscopic evaluation revealed no thrombosis in the stent-graft. She received the same dual antiplatelet therapy. .

A case of a late fatal complication after atrial fibrillation ablation related to a prolonged QT interval unmasked by atrial fibrillation ablation.

A 79-year-old woman with a history of atrial fibrillation (AF) ablation was referred to our hospital for ventricular fibrillation, which was terminated by an automated external defibrillator. The heart rate corrected QT interval was 489 ms. The electrocardiogram monitoring recorded a polymorphic ventricular tachycardia (VT) reproducibly induced by a single morphology premature ventricular contraction (PVC). Therefore, we performed a trigger PVC ablation and implanted an implantable cardioverter defibrillator. No VT events were observed for at least one year after the ablation. A prolonged QT interval after the AF ablation should be carefully noted because it could introduce fatal complications. .

Limited efficacy of a figure-of-eight suture for hemostasis after cryoballoon atrial fibrillation ablation with uninterrupted oral anticoagulants.

INTRODUCTION: There are limited data on the efficacy and safety of a figure-of-eight (FoE) suture technique after atrial fibrillation (AF) ablation with uninterrupted oral anticoagulants (OACs). This study evaluated the predictors of bleeding complications at the femoral puncture site after placing a FoE suture to achieve hemostasis after AF ablation with OACs. METHODS: We enrolled 287 consecutive patients who underwent a 1st session of AF ablation using radiofrequency or cryoballoon ablation. Hemostasis of the femoral puncture site was achieved using the FoE suture technique followed by a 4-h bed rest. We compared the various factors that might be correlated with bleeding complications between the patients with bleeding and those with non-bleeding complications. RESULTS: The bleeding complications were observed in 31 patients (11%). In the univariate analysis, cryoballoon ablation (52% vs. 29%, p = 0.009), HAS-BLED score (2.1 ± 1.0 vs. 1.7 ± 1.1, p = 0.030), and the CHA2DS2-VASc score (3.2 ± 1.5 vs. 2.6 ± 1.6, p = 0.049) were significantly associated with bleeding complications at the femoral puncture site. In the multivariate logistic regression analysis after an adjustment for antiplatelet therapy, cryoballoon ablation was an independent predictor of an increased incidence of the bleeding complications at the femoral puncture site (odds ratio 2.77, 95% CI 1.29-6.02, p = 0.009). CONCLUSION: Cryoballoon AF ablation was correlated with bleeding complications after a FoE suture technique with uninterrupted OACs.

Predictors of recurrence after pulmonary vein isolation in patients with normal left atrial diameter.

BACKGROUND: Enlarged left atrium (LA) is an established predictor of recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI), but occasionally recurrences of AF/atrial tachycardia (AT) are experienced in patients with normal left atrial diameter. Therefore, the predictors of AF recurrence and AF triggers were evaluated in patients with normal LA. METHODS: We enrolled 168 patients with normal LA (<40 mm) who underwent PVI. Various predictors were compared, including age, gender, coronary risk factors, brain natriuretic peptide (BNP), medications, echocardiographic parameters, and procedure parameters, between recurrence and nonrecurrence groups. RESULTS: The recurrence group consisted of 50 patients (29.8%). A univariate analysis demonstrated that the ratio of females, high BNP levels, severe tricuspid valve regurgitation (TR), and relapses of AF/AT during catheter ablation (CA) were significantly higher in the recurrence group. Multivariate analyses showed that a high BNP, severe TR, and AF/AT relapses during CA were independent factors associated with AF recurrence. During the second CA sessions, nonpulmonary vein (PV) triggers were therapeutic targets in 18 patients (46.2%), which was higher than that previously reported. CONCLUSION: A high BNP, severe TR and AF/AT relapses during CA may be correlated with AF recurrence after PVI in the patients with normal LA.

Predictors of cardiac function in acute heart failure patients with mid-range ejection fraction: AURORA study.

AIM: The factors correlated with prognosis in heart failure with mid-range ejection fraction (HFmrEF) is unclear, especially for acute heart failure (AHF) with HFmrEF. Thus, we investigated the factors correlated with the improvement in the ejection fraction (EF) over 1 year in AHF patients with HFmrEF. METHODS AND RESULTS: In Acute Heart Failure Registry in the Osaka Rosai Hospital, we examined 159 consecutive HFmrEF patients out of 1051 HF patients who were admitted to our hospital for AHF from January 2015 to December 2017. We divided them into improved EF (IM) group whose EF improved (≧10%) and non-IM group who had no improvement. We compared the baseline characteristics, echocardiographic data, medications, examinations for ischaemia, invasive treatments, and clinical outcomes between IM group and non-IM group. IM group consisted of 21 patients (20%). IM group had a significantly more de novo heart failure, higher serum albumin (Alb), lower EF, smaller left ventricular dimension during diastole, more frequent coronary angiogram during hospitalization, and coronary intervention. Multivariate analysis revealed that Alb, left ventricular dimension during diastole, and coronary angiogram performed during hospitalization were independently associated with the improvement in the EF. In addition, IM group had less rehospitalizations over 1 year and a greater reduction in the B-type natriuretic peptide level during the follow-up than non-IM group. CONCLUSIONS: In AHF patients with HFmrEF, we should evaluate for any ischaemic heart disease during hospitalization, especially in patients with non-enlarged left ventricular and non-reduced serum Alb. AHF patients with HFmrEF who showed improvement in the EF tended to have better prognosis than those without improvement.