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Yu Tamada,1– 3 Takeshi Inoue,2 Atsushi Sekine,4 Hiroyuki Toda,5 Minoru Takeshima,2,6 Masaaki Sasaki,3 Keisuke Shindome,5 Wataru Morita,5 Nagisa Kuyama,3 Susumu Ohmae3 1Department of Psychiatry, Toranomon Hospital Kajigaya, Kawasaki, Kanagawa, Japan; 2Department of Psychiatry, Tokyo Medical University, Tokyo, Japan; 3Department of Psychiatry, Toranomon Hospital, Tokyo, Japan; 4The Medical Foundation of Keishin-Kai, Kei Mental Clinic, Daisen, Akita, Japan; 5Department of Psychiatry, National Defense Medical College, Tokorozawa, Saitama, Japan; 6Shibata Hospital, Takaoka, Toyama, JapanCorrespondence: Yu TamadaDepartment of Psychiatry, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu-ku, Kawasaki, Kanagawa, 213-8587, JapanTel +81 44 877 5111Fax +81 44 877 5333Email y-tmd@umin.ac.jpPurpose: Melancholia has recently been re-evaluated, because patients with major depressive disorder (MDD) were found to be heterogeneous. However, the DSM-5 criteria for melancholia (DSM-MEL) have been criticized, because of the difficulty in clearly distinguishing between melancholic and non-melancholic depression using DSM-MEL. Psychomotor disturbance (PMD) is one of the most important, as well as one of the only measurable symptoms of melancholia. Parker et al developed the CORE measure, which assesses PMD as a behavioral characteristic. The aim of our study was to objectively identify the subjective symptoms of melancholia by analyzing the symptoms associated with PMD.Patients and Methods: A total of 106 participants with MDD were examined by psychiatrists. Multiple regression analysis was performed in which the total CORE score was the dependent variable, and items of the DSM-MEL and historically suggested melancholic features were independent variables.Results: The following five independent variables were able to predict the total CORE score: 1) feelings of having lost feeling, 2) depressive delusions, 3) perplexity, 4) indecisiveness, and 5) no aggression against others. These five variables were more strongly associated with the total CORE score than the DSM-MEL.Limitation: The major limitation of this study was that when choosing non-DSM melancholic signs and symptoms, we did not comprehensively evaluate and select the symptoms but chose items that are clinically important.Conclusion: We identified five subjective symptoms that were associated with PMD. These five symptoms may be clinically useful as diagnostic criteria for melancholia.Keywords: major depressive disorder, melancholic features, CORE measure, endogenous depression, diagnosis, psychomotor retardation

Background: 5-Aminolevulinic acid (5-ALA) is a naturally occurring metabolic precursor of heme, and 5-ALA combined with ferrous iron can induce heme oxygenase-1 (HO-1) in various cells. In this study, we investigated the cardioprotective effect of 5-ALA after myocardial ischemia/reperfusion (I/R) injury using a murine model., Methods and Results: Male C57BL/6 J mice (10-12 weeks of age and weighing 21-26 g) were pretreated with 100 mg/kg of 5-ALA hydrochloride and 157 mg/kg of sodium ferrous citrate (SFC) or vehicle 48 h, 24 h, and 1 h before I/R, and underwent 50 min of left coronary artery occlusion followed by reperfusion. Infarct area (IA) and area at risk (AAR) were determined by Evans blue and triphenyltetrazolium chloride double staining after reocclusion. Pre-administration with 5-ALA/SFC significantly reduced IA/AAR compared with placebo (34.0% vs. 51.7%, respectively; p = 0.001). Real-time PCR assay after reperfusion showed that mRNA expressions of TNF-α, IL-1β, and BNP were significantly lower, and that of HO-1 was significantly higher in the 5-ALA/SFC group than in the vehicle group in ischemic sites. An inhibition experiment revealed that zinc protoporphyrin IX, an inhibitor of HO-1, inhibited the cardioprotective effects of 5-ALA/SFC., Conclusions: These results suggest that 5-ALA/SFC might play a cardioprotective role in myocardial I/R injury by attenuating the inflammatory reaction by increasing the expression of HO-1., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms., Methods and Results: Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanized at either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. In vitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone., Conclusions: Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

Subclinical leaflet thrombosis (SLT) can be one of the causes of transcatheter heart valve (THV) failure after transcatheter aortic valve implantation (TAVI). We sought to clarify the formation process of SLT and thrombogenicity during the perioperative period of TAVI. This multicenter, prospective, single-arm interventional study enrolled 26 patients treated with edoxaban for atrial fibrillation and who underwent TAVI for severe aortic stenosis between September 2018 and September 2022. We investigated changes in maximal leaflet thickness detected by contrast-enhanced computed tomography between 1 week and 3 months after TAVI in 18 patients and measured the thrombogenicity by Total Thrombus-formation Analysis System (T-TAS) and flow stagnation volume by computational fluid dynamics (CFD) (n = 11). SLT was observed in 16.7% (3/18) at 1 week, but decreased to 5.9% (1/17) at 3 months after TAVI. Patients with SLT at 1 week had a significantly decreased maximal leaflet thickness compared to those without SLT. Thrombogenicity assessed by T-TAS decreased markedly at 1 week and tended to increase at 3 months. The stagnation volume assessed by CFD was positively associated with a higher maximum leaflet thickness. This study showed the course of leaflet thrombus formation and visualization of stagnation in neo-sinus of THV in the acute phase after TAVI., (© 2024. The Author(s).)

Aims: Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is often accompanied by atrial fibrillation (AF), atrial flutter (AFL), and atrial tachycardia (AT), which are difficult to control because beta-blockers and antiarrhythmic drugs can worsen heart failure (HF). This study aimed to investigate the outcomes of catheter ablation (CA) for AF/AFL/AT in patients with ATTRwt-CM and propose a treatment strategy for CA., Methods and Results: A cohort study was conducted on 233 patients diagnosed with ATTRwt-CM, including 54 who underwent CA for AF/AFL/AT. The background of each arrhythmia and the details of the CA and its outcomes were investigated. The recurrence-free rate of AF/AFL/AT overall in ATTRwt-CM patients with multiple CA was 70.1% at 1-year, 57.6% at 2-year, and 44.0% at 5-year follow-up, but CA significantly reduced all-cause mortality [hazard ratio (HR): 0.342, 95% confidence interval (CI): 0.133-0.876, P = 0.025], cardiovascular mortality (HR: 0.378, 95% CI: 0.146-0.981, P = 0.045), and HF hospitalization (HR: 0.488, 95% CI: 0.269-0.889, P = 0.019) compared with those without CA. There was no recurrence of the cavotricuspid isthmus (CTI)-dependent AFL, non-CTI-dependent simple AFL terminated by one linear ablation, and focal AT originating from the atrioventricular (AV) annulus or crista terminalis eventually. Twelve of 13 patients with paroxysmal AF and 27 of 29 patients with persistent AF did not have recurrence as AF. However, all three patients with non-CTI-dependent complex AFL not terminated by a single linear ablation and 10 of 13 cases with focal AT or multiple focal ATs originating beyond the AV annulus or crista terminalis recurred even after multiple CA., Conclusion: The outcomes of CA for ATTRwt-CM were acceptable, except for multiple focal AT and complex AFL. Catheter ablation may be aggressively considered as a treatment strategy with the expectation of improving mortality and hospitalization for HF., Competing Interests: Conflict of interest: H.K. has received grants from Medtronic Japan, Nihon Kohden, Abbott Medical Japan, Fukuda Denshi, Boston Scientific Japan, Japan Lifeline, Nipro, and Biotronik Japan. K.T. has received honoraria from Bayer Yakuhin, Daiichi Sankyo, Kowa, MSD, Sanofi, and Takeda Pharmaceutical and grants from Astellas Pharma, Abbott Vascular Japan, Bayer Yakuhin, Boehringer Ingelheim Japan, Boston Scientific Japan, Bristol-Myers, Chugai Pharmaceutical, Daiichi Sankyo, Goodman, Japan Lifeline, Medtronic Japan, Mitsubishi Tanabe Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Sanofi, Takeda Pharmaceutical, and Terumo. All remaining authors have declared no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Although tafamidis treatment improves prognosis in patients with wild-type transthyretin amyloid cardiomyopathy, an optimal surrogate marker monitoring its therapeutic effect remains unclear. This study investigated the association between changes in cardiac biomarkers, high-sensitivity cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) during the first year after tafamidis treatment and clinical outcomes., Methods and Results: In 101 patients with wild-type transthyretin amyloid cardiomyopathy receiving tafamidis at our institution, change in cardiac biomarkers from baseline to 1 year after tafamidis administration and its association with composite outcomes (composite of all-cause death and hospitalization attributable to heart failure) was assessed. During the follow-up period (median, 17 months), 16 (16%) patients experienced composite outcomes. The hs-cTnT level significantly decreased at 1 year after tafamidis treatment, unlike the BNP level. The frequencies of increased hs-cTnT and BNP levels were significantly higher in those with composite outcomes than in those without (44% versus 15%; P =0.01). Kaplan-Meier survival analysis showed that patients in whom both hs-cTnT and BNP levels increased at 1 year after tafamidis had a higher probability of composite outcomes compared with those with decreased hs-cTnT and BNP levels (log-rank P <0.01). Cox regression analysis identified increased hs-cTnT and BNP levels at 1 year after tafamidis administration as an independent predictor of higher cumulative risk of composite outcomes., Conclusions: Deterioration in cardiac biomarkers during the first year after tafamidis treatment predicted a worse prognosis, suggesting the utility of serial assessment of cardiac biomarkers for monitoring the therapeutic response to tafamidis in patients with wild-type transthyretin amyloid cardiomyopathy.

Aims: This study aims to evaluate the distribution of extracellular volume fraction detected via computed tomography, clinical characteristics of high extracellular volume fraction detected via computed tomography, and the rate of incidental detection of cardiac amyloidosis in patients undergoing cardiac computed tomography for coronary artery evaluation., Methods and Results: This study included 874 consecutive patients (mean age, 74.4 ± 7.1 years; men, 65%), comprising men aged ≥60 years and women aged ≥70 years, who had undergone cardiac computed tomography between January 2020 and September 2022. The mean extracellular volume fraction detected via computed tomography was 29.7 ± 5.2%, and 108 patients (12.4%) had an extracellular volume fraction detected via computed tomography of ≥35%. Older age (75.9 ± 8.2 years vs. 74.2 ± 6.9 years; P = 0.042), male sex (75.9% vs. 63.0%; P = 0.007), impaired left ventricular ejection fraction, increased high-sensitivity cardiac troponin T and B-type natriuretic peptide levels, and increased left ventricular thickness showed significant associations with an extracellular volume fraction detected via computed tomography of ≥35%. Cardiac amyloidosis was diagnosed incidentally in 15 patients based on an increase in extracellular volume fraction detected via computed tomography. The prevalence of cardiac amyloidosis was 1.7% (15/874) and 14.3% (15/105) in the entire study population and in patients with an extracellular volume fraction detected via computed tomography of ≥35%, respectively. An increase in the extracellular volume fraction detected via computed tomography was suggestive of cardiac amyloidosis., Conclusion: Elevated extracellular volume fraction detected via computed tomography, associated with elevated cardiac biomarker levels and myocardial structural changes, may lead to the incidental diagnosis of cardiac amyloidosis., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Subclinical leaflet thrombosis occasionally occurs after transcatheter aortic valve implantation (TAVI), but its exact etiology and relationship with thrombogenicity remain unknown. Methods and Results: This study enrolled 35 patients who underwent TAVI. Thrombogenicity was evaluated using a total thrombus-formation analysis system (T-TAS) to compute the thrombus-formation area under the curve (PL 18 -AUC 10 and AR 10 -AUC 30 ). Periprocedural thrombogenic parameters including T-TAS were investigated at pre-TAVI, 2 days, 7 days, and 3 months post-TAVI. Hypoattenuated leaflet thickening (HALT) and maximum leaflet thickness (MLT) were evaluated using contrast-enhanced computed tomography 7 days and 3 months post-TAVI. The associations between thrombogenicity and HALT or MLT were assessed. T-TAS parameters consistently decreased at 2 and 7 days post-TAVI, followed by improvement at 3 months. HALT was detected in 20% and 17% of patients at 7 days and 3 months, respectively, post-TAVI. The median MLT value was 1.60 mm at 7 days and 3 months post-TAVI. A significant positive correlation was observed between the decrease in the AR 10 -AUC 30 and MLT at 7 days post-TAVI. Univariate linear regression analysis revealed a decrease in the AR 10 -AUC 30 and an increase in the D-dimer level as a significant predictor of MLT deterioration. Conclusions: The findings suggested that a transient decrease in thrombogenicity following TAVI predicts leaflet thrombosis, implying that monitoring thrombogenicity may be useful for predicting progression of leaflet thrombosis., Competing Interests: K.K., K.T. are members of Circulation Reports’ Editorial Team. K.K. received Grants-in-Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, received remuneration for lectures from Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Novartis Pharma AG., Otsuka Pharmaceutical Co., Ltd., Bristol-Myers K.K., and Kowa Pharmaceutical Co. Ltd., received trust research/joint research funds from Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd., and received scholarship funds from Abbott Medical Co., Ltd. K.T. received significant research grants from Bayer Yakuhin, Ltd., Bristol-Myers K.K., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., CSL Behring K.K., JIMRO Co., Ltd., Alexion Pharmaceuticals, Inc., AnGes, Inc., PPD-Shin Nippon Biomedical Laboratories K.K., SUGI BEE GARDEN (International) Co., Ltd., Pfizer Japan Inc., scholarship funds from AMI Co., Ltd., Boehringer Ingelheim Japan, Daiichi Sankyo Co., Ltd., ONO Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Abbott Medical Co., Ltd., and ITI Co., Ltd. and honoraria from Amgen K.K., Abbott Medical Co., Ltd., AstraZeneca K.K., Bayer Yakuhin, Ltd., Daiichi Sankyo Co., Ltd., Medtronic Japan Co., Ltd., Kowa Pharmaceutical Co. Ltd., Kyowa Kirin Co., Ltd., Novartis Pharma K.K., Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., and Janssen Pharmaceutical K.K., and belongs to endowed departments donated by Abbott Japan Co., Ltd., Boston Scientific Japan K.K., Fides-one, Inc., GM Medical Co., Ltd., ITI Co., Ltd., Kaneka Medix Co., Ltd., NIPRO Corporation, Terumo Co, Ltd., Abbott Medical Co., Ltd., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., and Medtronic Japan Co., Ltd., (Copyright © 2023, THE JAPANESE CIRCULATION SOCIETY.)

Background: Carpal tunnel syndrome (CTS) is considered an early sign of cardiac amyloidosis (CA) because amyloid deposition is often confirmed in the tenosynovium removed during carpal tunnel release (CTR); however, the prevalence of concomitant CA is unclear., Methods and results: We prospectively examined 700 patients who underwent CTR and evaluated amyloid deposition after tenosynovium removal. Amyloid deposition was observed in 261 (37%) patients, who were significantly older and predominantly male (P<0.05). Of them, 120 agreed to cardiac screening. We performed 99 m Tc-labeled pyrophosphate ( 99 m Tc-PYP) scintigraphy in 12 patients who met either of the following criteria: (1) interventricular septal diameter (IVSd) ≥14 mm or (2) 12 mm ≤ IVSd < 14 mm with above-normal limits in high-sensitivity cardiac troponin T (hs-cTnT). Six patients (50%) had positive findings on 99 m Tc-PYP scintigraphy and were diagnosed with wild-type transthyretin CA. Concomitant CA was observed in 6/120 (5%) CTR patients with amyloid deposition and 50% (6/12) in patients with left ventricular hypertrophy (≥12 mm) with increased hs-cTnT levels., Conclusions: Amyloid deposition was frequently observed in the removed tenosynovium of elderly men with CTS. Cardiac screening may be useful for early diagnosis of CA in patients undergoing CTR with amyloid deposition.

Although the Japanese high bleeding risk criteria (J-HBR) were established to predict bleeding risk in patients undergoing percutaneous coronary intervention (PCI), the thrombogenicity in the J-HBR status remains unknown. Here, we examined the relationships among J-HBR status, thrombogenicity and bleeding events. This study was a retrospective analysis of 300 consecutive patients who underwent PCI. Blood samples obtained on the day of PCI were used in the total thrombus-formation analysis system (T-TAS) to investigate the thrombus-formation area under the curve (AUC; PL 18 -AUC 10 for platelet chip; AR 10 -AUC 30 for atheroma chip). The J-HBR score was calculated by adding 1 point for any major criterion and 0.5 point for any minor criterion. We assigned patients to three groups based on J-HBR status: a J-HBR-negative group (n = 80), a low score J-HBR-positive group (positive/low, n = 109), and a high score J-HBR-positive group (positive/high, n = 111). The primary end point was the 1-year incidence of bleeding events defined by the Bleeding Academic Research Consortium types 2, 3, or 5. Both PL 18 -AUC 10 and AR 10 -AUC 30 levels were lower in the J-HBR-positive/high group than the negative group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the J-HBR-positive/high group compared with the negative group. In addition, both T-TAS levels in J-HBR positivity were lower in those with bleeding events than in those without bleeding events. In multivariate Cox regression analyses, the J-HBR-positive/high status was significantly associated with 1-year bleeding events. In conclusion, the J-HBR-positive/high status could reflect low thrombogenicity as measured by T-TAS and high bleeding risk in patients undergoing PCI., (© 2023. The Author(s) under exclusive licence to Japanese Association of Cardiovascular Intervention and Therapeutics.)

Objectives: Clinically driven target lesion revascularization (CD-TLR) frequently occurs after endovascular therapy (EVT) in patients with chronic limb-threatening ischemia (CLTI). The total thrombus-formation analysis system (T-TAS) can quantitatively evaluate thrombogenicity. Therefore, we aimed to elucidate the association of the T-TAS parameters with CD-TLR., Methods: We analyzed 34 patients with CLTI and 62 patients without CLTI who had undergone EVT. Blood samples collected on the day of EVT were used in the T-TAS to compute the thrombus formation area under the curve for the first 10 minutes for the platelet chip tested at a flow rate of 24 μL/min (PL 24 -AUC 10 ) and area under the curve for the first 30 minutes for the atheroma chip tested at a flow rate of 10 μL/min (AR 10 -AUC 30 ). After EVT, clinical follow-up was performed, and the presence of CD-TLR was assessed., Results: During the follow-up period (median, 574 days), 10 patients (29%) in the CLTI group and 11 (18%) in the non-CLTI group had required CD-TLR. In the CLTI group, the patients with CD-TLR had had a higher AR 10 -AUC 30 vs those without (median, 1694 [interquartile range, 1657-1799] vs median, 1561 [interquartile range, 1412-1697]; P = .01). In contrast, the PL 24 -AUC 10 showed no significant differences when stratified by CD-TLR in either group. For the CLTI patients, multivariable Cox regression analysis using propensity score matching revealed that the AR 10 -AUC 30 was an independent predictor of CD-TLR even after adjusting for baseline demographics, lesion characteristics, and anticoagulant use (hazard ratio, 2.04; 95% confidence interval, 1.18-3.88; P = .01; per 100-unit increase). In contrast, for those without CLTI, neither the AR 10 -AUC 30 nor the PL 24 -AUC 10 was significantly associated with CD-TLR. Receiver operating characteristics curve analysis identified an AR 10 -AUC 30 level of 1646 as an optimal cutoff value to predict for CD-TLR (AUC, 0.85; sensitivity, 0.93; specificity, 0.56)., Conclusions: For patients with CLTI, but not for those without CLTI, the AR 10 -AUC 30 showed potential to predict for CD-TLR. This finding suggests that hypercoagulability might play a predominant role in the progression of CLTI and that anticoagulant therapy might be useful in preventing revascularization., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Although antithrombotic treatments are established for coronary artery disease (CAD), they increase the bleeding risk, especially in malnourished patients. The total thrombus-formation analysis system (T-TAS) is useful for the assessment of thrombogenicity in CAD patients. Here, we examined the relationships among malnutrition, thrombogenicity and 1-year bleeding events in patients undergoing percutaneous coronary intervention (PCI)., Methods and Results: This was a retrospective analysis of 300 consecutive CAD patients undergoing PCI. Blood samples obtained on the day of PCI were used in the T-TAS to compute the thrombus formation area under the curve. We assigned patients to two groups based on the geriatric nutritional risk index (GNRI): 102 patients to the lower GNRI group (≤98), 198 patients to the higher GNRI group (98<). The primary endpoint was the incidence of 1-year bleeding events defined by Bleeding Academic Research Consortium criteria types 2, 3, or 5. The T-TAS levels were lower in the lower GNRI group than in the higher GNRI group. Kaplan-Meier analysis showed worse 1-year bleeding event-free survival in the lower GNRI group compared with the higher GNRI group. The combined model of the GNRI and the Academic Research Consortium for High Bleeding Risk (ARC-HBR) had good calibration and discrimination for bleeding risk prediction. In addition, having a lower GNRI and ARC-HBR positivity was associated with 1-year bleeding events., Conclusion: A lower GNRI could reflect low thrombogenicity evaluated by the T-TAS and determine bleeding risk in combination with ARC-HBR positivity., Competing Interests: Declaration of competing interest Dr. Koichi Kaikita has received grants from Bayer Yakuhin, Ltd., and Daiichi-Sankyo Co., Ltd.; and honoraria from Bayer Yakuhin, Ltd. Dr. Kenichi Tsujita has received remuneration for lecture from Amgen Astellas BioPharma K.K., Bayer Yakuhin, Ltd., Bristol-Myers K.K., Daiichi Sankyo Co., Ltd., Kowa Pharmaceutical Co. Ltd., MSD K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., ITI Co., Ltd., and trust research/joint research funds from Bristol-Myers K.K., Kowa Pharmaceutical Co. Ltd., and scholarship fund from Abbott Medical Japan L.L.C, Abbott Vascular Japan Co., Ltd., Boston Scientific Japan K.K., Cardinal Health Japan, Chugai Pharmaceutical Co, Ltd., Fides-one, Inc., Fukuda Denshi Co., Ltd., Japan Lifeline Co., Ltd., Kaneka Medix Co., Ltd., Medtronic Japan Co., Ltd., Mitsubishi Tanabe Pharma, NIHON KOHDEN CORPORATION, NIPRO CORPORATION, Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., TERUMO Co, Ltd. The remaining authors have nothing to disclose., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background Statin-mediated efficacy of lowering low-density lipoprotein (LDL) cholesterol varies in each individual, and its diminished response is associated with worse outcomes. However, there is no established approach to predict hyporesponse to statins. PCSK9 (proprotein convertase subxilisin/kexin type 9) is a serine-protease associated with LDL metabolism, which circulates as mature and furin-cleaved PCSK9. Since mature PCSK9 more potently degrades the LDL receptor, its evaluation may enable the identification of statin hyporesponders. Methods and Results We analyzed 101 statin-naive patients with coronary artery disease who commenced a statin. PCSK9 subtypes at baseline and 1 month after statin use were measured by ELISA. Hyporesponse to statins was defined as a percent reduction in LDL cholesterol <15%. The relationship between each PCSK9 subtype level and hyporesponse to statins was investigated. Statins significantly lowered LDL cholesterol level (percent reduction, 40%±21%), whereas 11% of study participants exhibited a hyporeseponse to statins. Multivariable logistic regression analysis demonstrated that baseline mature PCSK9 level was an independent predictor for hyporesponse to statins even after adjusting clinical characteristics (mature PCSK9 per 10-ng/mL increase: odds ratio [OR], 1.12; 95% CI, 1.01-1.24 [ P =0.03]), whereas furin-cleaved level was not (per 10-ng/mL increase: OR, 1.37; 95% CI, 0.73-2.58 [ P =0.33]). Receiver operating characteristic curve analysis identified mature PCSK9 level of 228 ng/mL as an optimal cutoff to predict hyporesponse to statins (area under the curve, 0.73 [sensitivity, 0.91; specificity, 0.56]). Conclusions Baseline mature PCSK9 level >228 ng/mL is associated with hyporesponse to statins. This finding suggests that mature PCSK9 might be a potential determinant of hyporesponse to statins.

Background: Established antithrombotic therapies can increase bleeding risk, especially in hemodialysis (HD) patients. The Total Thrombus-formation Analysis System (T-TAS) is useful for evaluating thrombogenicity. The aim of this study was to examine the relationship between HD and thrombogenicity, or bleeding events in patients undergoing percutaneous coronary intervention (PCI)., Methods: In this retrospective cohort study, 300 patients undergoing elective PCI were enrolled between April 2017 and March 2019. Blood samples obtained on the day of PCI were analyzed with T-TAS to compute the thrombus formation area under the curve (AUC; PL 18 -AUC 10 for platelet chip; AR 10 -AUC 30 for atheroma chip). The patients were divided into three groups according to estimated glomerular filtration rate (eGFR): 33 HD patients, 124 non-HD patients with eGFR <60 mL/min/1.73m 2 , and 143 non-HD patients with eGFR ≥60. We examined the thrombogenicity and spontaneous bleeding events within 1-year post-PCI., Results: HD was significantly associated with both low PL 18 -AUC 10 and AR 10 -AUC 30 levels determined by T-TAS. Bleeding events defined by the Bleeding Academic Research Consortium criteria types 2, 3, or 5 occurred during follow-up in 27 patients (9.0%): 7 in HD, 10 in non-HD with eGFR <60, and 10 in non-HD with eGFR ≥60. Both T-TAS parameters in the patients with bleeding were lower compared with those in the patients without bleeding, and HD was significantly associated with 1-year bleeding events., Conclusions: The results suggested that HD patients undergoing PCI might be a predictor for low thrombogenicity measured by T-TAS and 1-year bleeding risk., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mitral annular calcification (MAC) is a common echocardiographic finding and an increasingly recognized cause of degenerative mitral stenosis (DMS). However, little is known about the clinical characteristics and disease progression in DMS, particularly in comparison with rheumatic mitral stenosis (RMS). We retrospectively reviewed 203 consecutive patients with mitral stenosis (113 with DMS and 90 with RMS) who underwent echocardiography at our institution between January 2014 and December 2017. We compared the clinical characteristics and disease progression between the 2 groups. In addition, we analyzed the predictors of disease progression (defined as annual progression rate of a mean gradient >0 mm Hg/year) among patients with DMS. Patients with DMS were significantly older and had higher prevalence of atherosclerotic comorbidities than those with RMS. During the median follow-up period of 2.2 years, the annual progression rates were comparable (0.8 ± 0.8 mm Hg/year in DMS vs 1.0 ± 1.2 mm Hg/year in RMS; p = 0.32) and were highly variable (0.0 to 3.5 mm Hg/year in DMS and 0.0 to 5.5 mm Hg/year in RMS) within both groups among disease progression. In DMS patients, atherosclerotic comorbidities and lower initial mean gradient were significantly associated with disease progression even after adjustment by age and sex. There was no significant difference in the disease progression according to the circumferential MAC severity determined by echocardiography among DMS. In conclusion, DMS disease progression was slow but highly variable, similar to that of RMS. In patients with DMS, the baseline MAC severity did not correlate with disease progression, suggesting the importance of follow-up echocardiography regardless of the MAC severity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Antithrombotic therapy is established for the treatment of various cardiovascular events. However, it has been shown to increase the bleeding risk. Total Thrombus-formation Analysis System (T-TAS) is reported to be useful for evaluating thrombogenicity. Here, we estimated whether T-TAS is useful for predicting bleeding events risk in patients undergoing percutaneous coronary intervention (PCI)., Methods: This was a retrospective, observational study at Kumamoto University Hospital between April 2017 and March 2019. Blood samples obtained on the day of PCI were used in T-TAS to compute the thrombus formation area under the curve (AUC) (AR 10 -AUC 30 , AUC for AR chip). We divided the study population into 2 groups according to the Academic Research Consortium for High Bleeding Risk (ARC-HBR) (182 patients in ARC-HBR positive, 118 in ARC-HBR negative). The primary endpoint was 1-year bleeding events that were defined by Bleeding Academic Research Consortium type2, 3, or 5., Results: The AR 10 -AUC 30 levels were significantly lower in the ARC-HBR positive group than in the ARC-HBR negative group (median [interquartile range] 1571.4 [1277.0-1745.3] vs. 1726.2 [1567.7-1799.6], p < 0.001). The combination of ARC-HBR and AR 10 -AUC 30 could discriminate the bleeding risk, and improved predictive capacity compared with ARC-HBR by c-statistics. Decision-curve analysis also revealed that combining AR 10 -AUC 30 with ARC-HBR ameliorated bleeding risk-prediction. In multivariate Cox hazards analyses, combining ARC-HBR with lower AR 10 -AUC 30 levels was significantly associated with 1-year bleeding events., Conclusions: The results highlight that AR 10 -AUC 30 evaluated by T-TAS could be a potentially useful marker for predicting high bleeding risk in patients undergoing PCI., (Copyright © 2020. Published by Elsevier B.V.)

A 74-year-old man was admitted to our hospital with chest pain and dyspnea associated with ST elevation in leads II, III and aVF. An echocardiogram showed an enlarged mass lesion measuring nearly 80 mm. Coronary angiography showed two giant coronary artery aneurysms (CAAs) in the right coronary artery (RCA). CAAs were also seen in the left main trunk and left anterior descending artery. Computed tomography showed the CAA in the RCA was ruptured into the right atrium. We therefore diagnosed this patient with multiple CAAs, myocardial infarction and coronary artery rupture. He underwent successful surgical excision and coronary bypass surgery.

We report a 6-month-old female infant with status convulsivus which appeared during intravenous drip infusion of aminophylline. She had an extremely high serum theophylline concentration (79 micrograms/ml), which was effectively reduced by plasmapheresis and dialysis. Three days later, she developed status convulsivus again, though her serum theophylline was undetectable at that time. A CT on 14th day of illness revealed mild widening of frontal sulci and Sylvian fissure. The patient apparently recovered her healthy condition, but psychomotor developmental delay, especially in speech and social behavior, was noted at the age of 2 years 6 months (DQ = 55). A delay of myelination was observed on brain MRI at 4 year 1 months, suggesting an irreversible brain injury caused by theophylline intoxication.

Traditional vegetables in Kyoto are a unique group of vegetables that have been cultivated in limited areas near Kyoto city. We compared the traditional vegetables in Kyoto with common vegetables for the bio-antimutagenicity of their extracts against UV-induced mutation of E. coli B/r WP2. Among the traditional vegetables in Kyoto, Kamo eggplant (Solanaceae) and Katsura oriental pickling melon (Cucurbitaceae) showed higher bio-antimutagenicity and yield in the n-hexane, chloroform and ethyl acetate fractions than their common vegetable counterparts. Shishigatani pumpkin (Cucurbitaceae) possessed bio-antimutagenicity in the chloroform and ethyl acetate fractions, but common pumpkin did not. Polyphenolic compounds in the ethyl acetate fraction of plants are known to be related to antimutagenicity. However, the intensity of bio-antimutagenicity was not correlated with the polyphenol content in the ethyl acetate fractions of the present vegetables. In particular, Kamo eggplant possessed both polyphenolic and non-polyphenolic bio-antimutagenic sub-fractions in the ethyl acetate fraction. In the aqueous fraction, taro (Dioscoreaceae) was the most capable among our samples, whether being of common or traditional origin. Consequently, it is considered, that some traditional vegetables in Kyoto are superior to common vegetables in their bio-antimutagenicity and that these could be used as starting materials to identify new bio-antimutagens.