A novel ryanodine receptor 2 inhibitor, M201-A, enhances natriuresis, renal function and lusi-inotropic actions: Preclinical and phase I study.

BACKGROUND AND PURPOSE: The ryanodine receptor 2 (RyR2) is present in both the heart and kidneys, and plays a crucial role in maintaining intracellular Ca2+ homeostasis in cells in these organs. This study aimed to investigate the impact of M201-A on RyR2, as well as studying its effects on cardiac and renal functions in preclinical and clinical studies. EXPERIMENTAL APPROACH: Following the administration of M201-A (1,4-benzothiazepine-1-oxide derivative), we monitored diastolic Ca2+ leak via RyR2 and intracellular Ca2+ concentration in isolated rat cardiomyocytes and in cardiac and renal function in animals. In a clinical study, M201-A was administered intravenously at doses of 0.2 and 0.4 mg·kg-1 once daily for 20 min for four consecutive days in healthy males, with the assessment of haemodynamic responses. KEY RESULTS: In rat heart cells, M201-A effectively inhibited spontaneous diastolic Ca2+ leakage through RyR2 and exhibited positive lusi-inotropic effects on the rat heart. Additionally, it enhanced natriuresis and improved renal function in dogs. In human clinical studies, when administered intravenously, M201-A demonstrated an increase in natriuresis, glomerular filtration rate and creatinine clearance, while maintaining acceptable levels of drug safety and tolerability. CONCLUSIONS AND IMPLICATIONS: The novel drug M201-A inhibited diastolic Ca2+ leak via RyR2, improved cardiac lusi-inotropic effects in rats, and enhanced natriuresis and renal function in humans. These findings suggest that this drug may offer a potential new treatment option for chronic kidney disease and heart failure.

Cardiovascular Outcomes after Paclitaxel-Coated Balloon Angioplasty versus Drug-Eluting Stent Placement for Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

Background: We conducted a systematic review and meta-analysis to examine the feasibility of paclitaxel-coated balloon (PCB) angioplasty for de novo lesions in patients with acute coronary syndrome (ACS) by comparing with drug-eluting stent (DES) placement. Methods: By a systematic literature search, nine (five randomized controlled, two retrospective propensity-score matched, and two retrospective baseline-balanced) studies comparing the midterm clinical and angiographic outcomes after PCB angioplasty and DES placement were included, yielding 974 and 1130 ACS cases in PCB and DES groups, respectively. Major adverse cardiac event (MACE) was defined as a composite of cardiac mortality (CM), all-cause mortality (ACM), myocardial infarction (MI), target vessel revascularization (TVR), and target lesion revascularization (TLR). Late luminal loss (LLL) and bleeding events (BLD) were also estimated. Results: The frequencies of MACE in PCB and DES groups were 8.42% and 10.62%, respectively. PCB angioplasty had no significant impacts on all of MACE (risk ratio: 0.90, 95%CI: 0.68-1.18, p = 0.44), CM, ACM, MI, TVR, TLR, BLD, and LLL, compared to DES placement in random-effects model. Conclusions: The present systematic review and meta-analysis showed the feasibility of PCB angioplasty for the de novo lesions in patients with ACS in comparison with DES placement by the emergent procedures.

Chronic Effect of HotBalloon-Based Wide Planar Ablation on Epicardial Adipose Tissue in Persistent Atrial Fibrillation.

Background: Adverse atrial remodeling, including epicardial adipose tissue (EAT) deposition in the left atrium (LA), is implicated in atrial fibrillation (AF). Radiofrequency hotballoon (RHB) ablation can produce wide planar lesions because the balloon is highly compliant; however, chronic effects of RHB ablation on structural remodeling remain unknown. This clinical-experimental investigation characterized chronic effects of RHB ablation on EAT in persistent AF (PsAF). Methods and Results: The clinical study involved 91 patients (obese, n=30; non-obese, n=61) undergoing RHB ablation for PsAF. LA-EAT was assessed from computed tomography images obtained before ablation and 6 months later. Tissue effects of RHB ablation were explored in a chronic swine model. RHB ablation significantly reduced LA volume (mean [±SD] 177.7±29.7 vs. 138.4±29.6 mL; P<0.001) and LA-EAT volume (median [interquartile range] 22.0 [12.4-33.3] vs. 16.5 [7.9-25.8] mL; P<0.001). The reduction in EAT was significantly greater in the pulmonary vein (PV) antrum than in other LA regions (37.9% vs. 15.8%; P<0.001). The percentage reduction in PV antrum EAT was equivalent between obese and non-obese patients, as was the postablation success rate (73% vs. 70%; P=0.77). RHB ablation produced transmural lesions reaching the pigs' epicardial fat region. Conclusions: RHB-based planar-transmural lesions altered the structurally remodeled LA, including EAT. Further studies are needed to determine whether factors other than PV isolation contribute to the clinical success of RHB ablation.

Deep learning-based model detects atrial septal defects from electrocardiography: a cross-sectional multicenter hospital-based study.

Background: Atrial septal defect (ASD) increases the risk of adverse cardiovascular outcomes. Despite the potential for risk mitigation through minimally invasive percutaneous closure, ASD remains underdiagnosed due to subtle symptoms and examination findings. To bridge this diagnostic gap, we propose a novel screening strategy aimed at early detection and enhanced diagnosis through the implementation of a convolutional neural network (CNN) to identify ASD from 12-lead electrocardiography (ECG). Methods: ECGs were collected from patients with at least one recorded echocardiogram at 3 hospitals from 2 continents (Keio University Hospital from July 2011 to December 2020, Brigham and Women's Hospital from January 2015 to December 2020, and Dokkyo Medical University Saitama Medical Center from January 2010 and December 2021). ECGs from patients with a diagnosis of ASD were labeled as positive cases while the remainder were labeled as negative. ECGs after the closure of ASD were excluded. After randomly splitting the ECGs into 3 datasets (50% derivation, 20% validation, and 30% test) with no patient overlap, a CNN-based model was trained using the derivation datasets from 2 hospitals and was tested on held-out datasets along with an external validation on the 3rd hospital. All eligible ECGs were used for derivation and validation whereas the earliest ECG for each patient was used for the test and external validation. The discrimination of ASD was assessed by the area under the receiver operating characteristic curve (AUROC). Multiple subgroups were examined to identify any heterogeneity. Findings: A total of 671,201 ECGs from 80,947 patients were collected from the 3 institutions. The AUROC for detecting ASD was 0.85-0.90 across the 3 hospitals. The subgroup analysis showed excellent performance across various characteristics Screening simulation using the model greatly increased sensitivity from 80.6% to 93.7% at specificity 33.6% when compared to using overt ECG abnormalities. Interpretation: A CNN-based model using 12-lead ECG successfully identified the presence of ASD with excellent generalizability across institutions from 2 separate continents. Funding: This work was supported by research grants from JST (JPMJPF2101), JSR corporation, Taiju Life Social Welfare Foundation, Kondou Kinen Medical Foundation, Research fund of Mitsukoshi health and welfare foundation, Tokai University School of Medicine Project Research and Internal Medicine Project Research, Secom Science and Technology Foundation, and Grants from AMED (JP23hma922012 and JP23ym0126813). This work was partially supported by One Brave Idea, co-funded by the American Heart Association and Verily with significant support from AstraZeneca and pillar support from Quest Diagnostics.

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 ).

Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA).

INTRODUCTION: Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. METHODS: This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. RESULTS: Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was - 35.8% (95% confidence interval [CI] - 39.7% to - 32.0%, P < 0.001), with approximately three quarters of patients achieving an SUA level of ≤ 6.0 mg/dL at week 24. The proportional changes from baseline in the geometric mean of CAVI and d-ROMs at week 24 were 0.96 (95% CI 0.92 to 1.00, P = 0.044) and 0.96 (95% CI 0.92 to 1.00, P = 0.044), respectively. CONCLUSION: In addition to meaningful SUA-lowering effects, 24 weeks of dotinurad therapy may favorably affect arterial stiffness and oxidative stress markers, suggesting off-target vascular protection of dotinurad. Further research is expected to verify our findings and elucidate the entire off-target effects of dotinurad. Trial registration jRCTs021210013, registration date June 24, 2021.

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.

Prognostic Impacts of CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HS Scores on Clinical Outcomes After Elective Drug-Eluting Stent Placement for De Novo Coronary Stenosis.

Background: The prognostic impact of CHADS2, CHA2DS2-VASc, and CHA2DS2-VASc-HS scores on clinical outcomes after drug-eluting stent (DES) placement has not been fully elucidated. Methods and Results: The present study was a retrospective, non-randomized, single-center, and lesion-based study. Target lesion failure (TLF), comprising cardiac death, non-fatal myocardial infarction, and target vessel revascularization, occurred in 7.1% of 872 consecutive de novo coronary lesions in 586 patients. These patients were electively and exclusively treated by DESs from January 2016 to January 2022 until July 2022 with a mean (±SD) observational interval of 411±438 days. Multivariate Cox proportional hazard analysis revealed that CHA2DS2-VASc-HS scores ≥7 (hazard ratio [HR] 1.800; 95% CI 1.06-3.05; P=0.029) was a significant predictor of cumulative TLF among 24 variables evaluated. CHADS2 scores ≥2 (HR 3.213; 95% CI 1.32-7.80; P=0.010) and CHA2DS2-VASc scores ≥5 (HR 1.980; 95% CI 1.10-3.55; P=0.022) were also significant in the multivariate analysis. Pairwise comparisons of receiver operating characteristic curves for CHADS2 score ≥2, CHA2DS2-VASc score ≥5, and CHA2DS2-VASc-HS score ≥7 showed they were equivalent in terms of predicting the incidence of TLF, with areas under the curve of 0.568, 0.575, and 0.573, respectively. Conclusions: All 3 cardiocerebrovascular thromboembolism risk scores were strong predictors of the incidence of cumulative mid-term TLF after elective DES placement, with cut-off values of 2, 5, and 7, respectively, and equivalent prognostic impacts.

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.

Is creation of a fully circumferential lesion set necessary for laser balloon ablation-based pulmonary vein isolation?

BACKGROUND: Despite reports of remote pulmonary vein (PV) stenosis after visually guided laser balloon (VGLB) ablation, circumferential (360°) lesion sets are routinely performed. This study aimed to determine whether fully circumferential lesion creations are required for all PVs to achieve PV isolations (PVIs) and to determine PV's vulnerability to chronic-phase stenosis. METHODS: Fifty-one patients with paroxysmal atrial fibrillation underwent mapping-guided PVIs using circular mapping catheters. VGLB ablation was performed circumferentially beginning at the 12 o'clock position and continued clockwise or counterclockwise. PVIs obtained within the bounds of the first half of the circumferential lesion (≤ 180°) were defined as "early PVIs." RESULTS: "Early PVIs" were documented in real time for 39% (80/204) of the PVs and at a significantly greater frequency among lower PVs than upper PVs (60.1% vs. 17.6%; p < 0.0001). The PV sleeve length, PV diameter, and isolation of ipsilateral PVs within a semicircular lesion set were identified as predictors of an "early PVI" phenomenon. The amount of energy delivered to the lower PVs was significantly less than that to the upper PVs (5553 [5089-6188] vs. 3559 [2793-4380] J; p < 0.0001), but the incidence of narrowing of the lower PVs at 6 months was comparable to that of the upper PVs (p = 0.73). CONCLUSION: Our study revealed electrical isolations of more than 60% of the lower PVs while creating the first half of the circumferential lesions. Crosstalk via the carina region was presumably involved due to the preceding upper PVI. Further study is needed to determine whether energy delivery adjustments are needed for lower PVs to avoid chronic narrowing.

Canagliflozin independently reduced plasma volume from conventional diuretics in patients with type 2 diabetes and chronic heart failure: a subanalysis of the CANDLE trial.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I-II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: -4.00% vs. 1.46% (p = 0.020) for the diuretic group and -6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.

Effect of ipragliflozin on carotid intima-media thickness in patients with type 2 diabetes: a multicenter, randomized, controlled trial.

AIMS: To examine the effects of a 24-month treatment with ipragliflozin on carotid intima-media thickness (IMT) in type 2 diabetes patients. METHODS AND RESULTS: In this multicenter, prospective, randomized, open-label, and blinded-endpoint investigator-initiated clinical trial, adults with type 2 diabetes and haemoglobin A1C (HbA1c) of 6.0-10.0% (42-86 mmol/mol) were randomized equally to ipragliflozin (50 mg daily) and non-sodium-glucose cotransporter-2 (SGLT2) inhibitor use of standard-care (control group) for type 2 diabetes and were followed-up to 24 months. The primary endpoint was the change in mean common carotid artery IMT (CCA-IMT) from baseline to 24 months. A total of 482 patients were equally allocated to the ipragliflozin (N = 241) and control (N = 241) groups, and 464 patients (median age 68 years, female 31.7%, median type 2 diabetes duration 8 years, median HbA1c 7.3%) were included in the analyses. For the primary endpoint, the changes in the mean CCA-IMT from baseline to 24 months were 0.0013 [95% confidence interval (CI), -0.0155-0.0182] mm and 0.0015 (95% CI, -0.0155-0.0184) mm in the ipragliflozin and control groups, respectively, with an estimated group difference (ipragliflozin-control) of -0.0001 mm (95% CI, -0.0191-0.0189; P = 0.989). A group difference in HbA1c change at 24 months was also non-significant between the treatment groups [-0.1% (95% CI, -0.2-0.1); P = 0.359]. CONCLUSION: Twenty-four months of ipragliflozin treatment did not affect carotid IMT status in patients with type 2 diabetes recruited in the PROTECT study, relative to the non-SGLT2 inhibitor-use standard care for type 2 diabetes.

Midterm safety and efficacy of elective drug-coated balloon angioplasty in comparison to drug-eluting stents for unrestrictive de novo coronary lesions: A single center retrospective study.

BACKGROUND: The safety and efficacy of elective drug-coated balloon (DCB) angioplasty for unrestrictive de novo coronary stenosis in daily practice is not fully understood, especially in comparison to those of drug-eluting stents (DESs). METHODS: A total of 588 consecutive de novo coronary stenotic lesions electively and successfully treated with either DCB (n = 275) or DESs (n = 313) between January 2016 and December 2019 at our medical center were included. The primary safety endpoint was the incidence of target lesion failure (TLF), comprising cardiac death, non-fatal myocardial infarction, and target vessel revascularization. The secondary angiographic efficacy endpoint was angiographic restenosis frequency, defined as a follow-up percent diameter stenosis of >50. The endpoints were compared after baseline adjustment using propensity score matching. In addition, the frequency and predictors of late lumen enlargement (LLE), defined as minus late luminal loss, were examined in 201 crude angiographic follow-up lesions after DCB angioplasty. RESULTS: A total of 31 baseline parameters were adjusted to analyze 177 lesions in each group. The TLF frequencies (DCB group: 9.6 % during a mean observational interval of 789 ±â€¯488 days vs. DES group: 10.2 %, 846 ±â€¯484 days, p = 0.202) and cumulative TLF-free ratios of both groups were not significantly different (p = 0.892, log-rank test). The angiographic restenosis frequency in the DCB group (6.3 %, n = 128) was not significantly different from that of the DES group (10.1 %, n = 100, p = 0.593). LLE was observed in 45.3 % of entire lesions, and a type-A dissection was a significant predictor of LLE among 23 variables (odds ratio: 3.02, 95 % CI: 1.31-6.95, p = 0.010). CONCLUSIONS: The present single-center retrospective study revealed statistically equivalent midterm clinical safety and angiographic efficacy among both elective DCB angioplasty and DESs placements in the treatment of unrestrictive de novo coronary lesions. In our daily practice environment, LLE was achieved in approximately half after DCB angioplasty.

Usefulness of a Perfusion Balloon for Intraprocedural Stent Thrombosis in a Patient With ST-Segment Elevated Myocardial Infarction Complicated With Cardiogenic Shock.

Intraprocedural stent thrombosis is a rare but serious complication of reperfusion therapy for acute coronary syndrome. There is currently no consensus on the intraprocedural management of intraprocedural stent thrombosis. It is difficult to attain thrombolysis in myocardial infarction flow grade 3, particularly in cases of cardiogenic shock. A 49-year-old man who presented with anterior ST-segment elevated acute myocardial infarction with cardiogenic shock underwent emergency percutaneous coronary intervention to diffuse proximal lesions in the left anterior descending artery under the support of intra-aortic balloon pumping. Intraprocedural stent thrombosis occurred following the postdilations with a 3.5- × 38-mm everolimus-eluting stent. Despite administration of argatroban and nitroprusside, and after frequent balloon inflations using 3.5-mm noncompliant balloons and thrombectomy, the no-reflow phenomenon was repetitively established. However, after brief and prolonged balloon inflations using 3.5- and 3-mm Ryusei perfusion balloon catheters (Kaneka Medix), the diffusely protruded thrombus inside the stent regressed, and thrombolysis in myocardial infarction flow grade 3 was obtained. The final intravascular ultrasound image showed a well-suppressed, in-stent thrombus and 24% gain of stent area (from 7.5 to 9.3 mm2). A Ryusei perfusion balloon enabled frequent, long inflation times without deteriorating hemodynamics during reperfusion in ST-segment elevated acute myocardial infarction complicated with cardiogenic shock. Thus, extended balloon inflation using a perfusion balloon is deemed a viable option not only for intraprocedural stent thrombosis but also for cases with a high burden of thrombi during the primary stenting procedure for patients with acute coronary syndrome.

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.

A case of steroid-resistant cystitis as an immune-related adverse event during treatment with nivolumab for lung cancer, which was successfully treated with infliximab.

Introduction: Immune checkpoint inhibitors are widely used in various cancers as a standard treatment. However, while various immune-related adverse events related to immune checkpoint inhibitors have been reported, there are few reports of lower urinary tract symptoms. Case presentation: The patient was a 60-year-old man with primary lung cancer who was receiving long-term nivolumab therapy. He was referred to our department due to the sudden onset of glans penile pain and micturition pain. We suspected non-bacterial cystitis as an immune-related adverse event caused by nivolumab and were able to treat it by administering prednisolone. While his symptoms and findings on cystoscopy recurred during prednisolone therapy, we were able to treat him again by administering an additional dose of infliximab. Conclusion: A few reports have described cases of immune checkpoint inhibitor-induced cystitis for which prednisolone was effective. This report is the first to describe cystitis as a steroid-resistant immune-related adverse event.

[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.