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Background: Anticoagulation therapy for atrial fibrillation (AF) has undergone major changes following the introduction of direct oral anticoagulants (DOAC) in 2011. However, the transition of anticoagulation therapy for AF patients with severe renal dysfunction remains to be elucidated., Methods and Results: Follow-up data, including creatinine clearance (CrCl), were available for 3,706 patients in the Fushimi AF Registry. We divided patients into 3 groups based on CrCl as follows: (1) CrCl ≥50 mL/min; (2) 50 mL/min>CrCl≥30 mL/min; and (3) CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50>CrCl≥30 mL/min, prescription of oral anticoagulants increased year-by-year from 2011 to 2021 with a growing proportion of DOAC; however, the prescription of oral anticoagulants remained almost unchanged in those with CrCl <30 mL/min. In patients with CrCl ≥50 mL/min and 50 mL/min>CrCl≥30 mL/min, the incidence of adverse events, including stroke/systemic embolism and major bleeding, was lower among patients enrolled after 2014 than before 2013. However, these trends were not seen in patients with CrCl <30 mL/min., Conclusions: Despite the increased use of DOAC in patients with AF since 2011, anticoagulation therapy for AF patients with severe renal dysfunction has largely remained unchanged, and a reduction in adverse events in those patients has not been observed.

Triple-negative breast cancer (TNBC) presents limited therapeutic options and is associated with poor prognosis. Early detection and the development of novel therapeutic agents are therefore imperative. Fibroblast activation protein (FAP) is a membrane protein expressed on cancer-associated fibroblasts (CAFs) that plays an essential role in TNBC proliferation, migration, and invasion. Consequently, it is hypothesized that the Astatine ( 211 At)-labeled FAP inhibitor (FAPI) selectively exerts anti-tumor effects through alpha-particle emission. In this study, we aimed to assess its theranostic capabilities by integrating [ 18 F]FAPI-74 PET imaging with targeted alpha therapy using [ 211 At]FAPI1 in TNBC models. Mice xenografts were established by transplanting MDA-MB-231 and HT1080 cells (control). As a parallel diagnostic method, [ 18 F]FAPI-74 was administered for PET imaging to validate FAP expression. A single dose of [ 211 At]FAPI1 (1.04 ± 0.10 MBq) was administered to evaluate the therapeutic efficacy. [ 18 F]FAPI-74 exhibited high accumulation in MDA-MB-231 xenografts, and FAP expression was pathologically confirmed via immunostaining. The group that received [ 211 At]FAPI1 (n = 11) demonstrated a significantly enhanced anti-tumor effect compared with the control group (n = 7) ( p = 0.002). In conclusion, [ 18 F]FAPI-74 PET imaging was successfully used to diagnose FAP expression, and as [ 211 At]FAPI1 showed promising therapeutic efficacy in TNBC models, it is expected to be a viable therapeutic option.

Objectives : Coronary microvascular dysfunction (CMD) is associated with many heart diseases, including heart failure (HF) with preserved ejection fraction (HFpEF). Invasive examinations for CMD detection are difficult in older patients with HFpEF, and the decision criteria for noninvasive CMD measurements are unclear. We aimed to identify alternative factors in the possible involvement of CMD in the progression and prognosis of HFpEF. Methods : We analyzed 607 patients with HFpEF who were hospitalized for acute decompensated HF without a history of coronary artery disease (CAD). Blood tests and transthoracic echocardiography were performed. We focused on left ventricular hypertrophy (LVH) and coronary perfusion pressure (diastolic blood pressure, dBP). Results : The patients with LVH showed reduced diastolic function (E/e') and a lower incidence of atrial fibrillation (AF) compared with those without LVH, with no differences in age or dBP. No differences were observed in all-cause mortality between patients with low and high dBP without LVH. In the patients with LVH, the incidence of all-cause mortality was significantly higher, with a lower incidence of AF, reduced renal function, and higher C-reactive protein levels in those with low dBP than in those with high dBP. The comprehensive diastolic functional index, diastolic elastance/arterial elastance, was markedly higher in the patients with LVH, especially in those with all-cause mortality. This index, but not E/e', was a significant prognostic index in the multivariate Cox hazard analysis when adjusting for age, sex and N-terminal pro-brain natriuretic peptide levels. Conclusions : LVH and dBP were clinically important factors in elderly HFpEF patients without a history of CAD.

Some patients with atrial fibrillation (AF), albeit less frequently, may regress from sustained to paroxysmal type. We sought to investigate how the regression of AF is associated with outcomes. Among the AF patients enrolled in the Fushimi AF Registry who were identified as having sustained AF at baseline, conversion of sustained to paroxysmal AF during follow-up was defined as AF regression. Major adverse cardiovascular events (MACE) were defined as a composite of cardiac death, myocardial infarction, ischemic stroke, systemic embolism, or hospitalization due to heart failure. Among 2,261 patients with sustained AF at baseline, AF regression was observed in 214 (9.5%) patients over a median follow-up period of 5.8 years (1.78% per patient-year). The annual incidence of MACE in patients with AF regression was significantly lower than those without (3.47% vs. 6.59% per patient-year, P < 0.001; adjusted hazard ratio [HR], 0.53, 95% confidence interval [CI], 0.38-0.72). Furthermore, AF regression was significantly associated with reduced risk of MACE during and after the regression period from sustained to paroxysmal forms (during regression period: adjusted HR, 0.45; 95% CI, 0.22-0.90; after regression period: adjusted HR, 0.43; 95% CI, 0.26-0.67). The incidence of MACE was comparable between spontaneous regression (35/178: 19.7%) and therapy-associated regression (either receiving catheter ablation or antiarrhythmic drugs before the regression) (7/36: 19.4%) (P=0.98). Regression of AF was associated with a lower incidence of adverse cardiovascular events. The risk of adverse events decreased significantly during the regression period and its reduction level persisted after regression. URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000005834., Competing Interests: Declaration of competing interest Dr. Akao received lecture fees from Pfizer, Bristol-Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Neuromodulation through spinal cord stimulation (SCS) is a therapeutic option for relieving leg pain and improving the chances of limb salvage in patients with intractable chronic limb-threatening ischemia (CLTI); however, there is no consensus on its indications., Objective: The aim of this study was to assess the clinical outcomes of SCS in patients with intractable leg pain caused by various diseases treated in the department of cardiovascular medicine in Japan., Methods: This was a retrospective study of patients who underwent SCS for pain management. Patients were considered eligible for the therapy if they met the following criteria: (1) intractable leg pain (numerical rating scale [NRS] score of 10), (2) no revascularization option, and (3) no septicemia., Results: Twenty patients (mean age: 77 years; men/women: 11/9) were included in this study. The NRS score of the patients significantly reduced from 10 ± 0 before procedure to 4 ± 3 at discharge (p < 0.001). The clinical response rate of the entire cohort was 65% (13/20) at 17 ± 14 months after implantation; however, patients with intractable CLTI showed a low response rate (45%), whereas those with subacute limb ischemia showed a high response rate (100%). A multivariable regression analysis showed that hemoglobin level was significantly associated with treatment response, even after adjusting for age and sex (p = 0.026). The area under the receiver operating characteristic curve for the correlation between hemoglobin level (cutoff, 11.4 g/dL) and clinical response to SCS was 0.824 (0.619-1)., Conclusions: SCS can reduce clinical symptoms in majority of patients with intractable leg pain. Although implantation of an SCS device has been shown to improve microvascular perfusion insufficiency, the correlation between hemoglobin level and the clinical effect of SCS indicates that a preserved microcirculatory vascular bed is essential for the therapy to be effective., (© 2024 World Institute of Pain.)

Bone metastasis significantly affects the quality of life of patients with metastatic breast cancer, and can shorten overall survival. Identifying patients with early-stage breast cancer at high risk for bone metastasis and preventing bone metastasis may lead to a better quality of life and prolonged survival. The present study investigated whether serum tartrate-resistant acid phosphatase-5b (TRACP-5b), a bone turnover marker, can be a prognostic factor for bone metastasis. Female patients who underwent resectable breast surgery between May 2002 and August 2006 were consecutively investigated. A total of 304 patients with a median follow-up of 3,722 days were retrospectively analyzed. TRACP-5b levels in sera prepared from patients' blood drawn preoperatively without any presurgical treatments were measured using an enzyme-linked immunosorbent assay. The cutoff of TRACP-5b levels, in order to separate patients into high and low TRACP-5b groups, was set at median (347 mU/dl). The associations of clinicopathological factors, including TRACP-5b, with bone metastasis-free interval (BMFI), which was defined as the duration between surgery and the diagnosis of bone metastasis at any time point, were examined. Multivariate analysis of various clinicopathological features revealed that lymph node metastasis and histological grade were independent factors associated with BMFI (P=0.017 and 0.030, respectively). In patients with node-positive breast cancer (n=114), a high TRACP-5b level and a high grade were significantly and independently associated with worse BMFI (log-rank P=0.041 and 0.011, respectively). In conclusion, these findings indicated that TRACP-5b may predict bone metastasis in patients with node-positive breast cancer., Competing Interests: Nittobo Co., Ltd. funded TRACP-5b measurements for 111 out of 320 samples. MS and KS are conducting joint research unrelated to this study with Nittobo Co., Ltd. The other authors have no potential conflicts of interest., (Copyright: © 2024 Shimoda et al.)

Purpose: Breast cancer tumors frequently have intratumoral heterogeneity (ITH). Tumors with high ITH cause therapeutic resistance and have human epidermal growth factor receptor 2 (HER2) heterogeneity in response to HER2-targeted therapies. This study aimed to investigate whether high HER2 heterogeneity levels were clinically related to a poor prognosis for HER2-targeted adjuvant therapy resistance in primary breast cancers., Methods: This study included patients with primary breast cancer ( n = 251) treated with adjuvant HER2-targeted therapies. HER2 heterogeneity was manifested by the shape of HER2 fluorescence in situ hybridization amplification (FISH) distributed histograms with the HER2 gene copy number within a tumor sample. Each tumor was classified into a biphasic grade graph (high heterogeneity [HH]) group or a monophasic grade graph (low heterogeneity [LH]) group based on heterogeneity. Both groups were evaluated for disease-free survival (DFS) and overall survival (OS) for a median of ten years of annual follow-up., Results: Of 251 patients with HER2-positive breast cancer, 46 (18.3%) and 205 (81.7%) were classified into the HH and LH groups, respectively. The HH group had more distant metastases and a poorer prognosis than the LH group (DFS: p < 0.001 (HH:63% vs. LH:91% at 10 years) and for the OS: p = 0.012 (HH:78% vs. LH:95% at 10 years)., Conclusions: High HER2 heterogeneity is a poor prognostic factor in patients with HER2-positive breast cancer. A novel approach to heterogeneity, which is manifested by the shape of HER2 FISH distributions, might be clinically useful in the prognosis prediction of patients after HER2 adjuvant therapy., Competing Interests: The authors declare no conflicts of interest.

Aims: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little is known regarding the risk stratification for incident HF in AF patients, especially with preserved left ventricular ejection fraction (LVEF)., Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients. From the registry, 3002 non-valvular AF patients with preserved LVEF and with the data of antero-posterior left atrial diameter (LAD) at enrolment were investigated. Patients were stratified by LAD (<40, 40-44, 45-49, and ≥50 mm) with backgrounds and HF hospitalization incidences compared between groups. Of 3002 patients [mean age, 73.5 ± 10.7 years; women, 1226 (41%); paroxysmal AF, 1579 (53%); and mean CHA 2 DS 2 -VASc score, 3.3 ± 1.7], the mean LAD was 43 ± 8 mm. Patients with larger LAD were older and less often paroxysmal AF, with a higher CHA 2 DS 2 -VASc score (all P < 0.001). Heart failure hospitalization occurred in 412 patients during the median follow-up period of 6.0 years. Larger LAD was independently associated with a higher HF hospitalization risk [LAD ≥ 50 mm: hazard ratio (HR), 2.36; 95% confidence interval (CI), 1.75-3.18; LAD 45-49 mm: HR, 1.84; 95% CI, 1.37-2.46; and LAD 40-44 mm: HR, 1.34; 95% CI, 1.01-1.78, compared with LAD < 40 mm) after adjustment by age, sex, AF type, and CHA 2 DS 2 -VASc score. These results were also consistent across major subgroups, showing no significant interaction., Conclusion: Left atrial diameter is significantly associated with the risk of incident HF in AF patients with preserved LVEF, suggesting the utility of LAD regarding HF risk stratification for these patients., Competing Interests: Conflict of interest: Ma.A. received lecture fees from Pfizer, Bristol Myers Squibb, Boehringer Ingelheim, Bayer Healthcare, and Daiichi Sankyo. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Acute purulent pericarditis is a rare infection in developed countries. We herein report a case with diabetic nephropathy under maintenance hemodialysis who suffered from acute purulent pericarditis caused by methicillin-resistant Staphylococcus aureus (MRSA). The treatment of purulent pericarditis mainly involves rapid administration of appropriate antibiotics and drainage. However, in this case, the patient was unresponsive to vancomycin and performing early surgical intervention was challenging due to highly pathogenic MRSA. Therefore, we performed pericardial fenestration in the chronic phase to suppress the risk of fatal secondary infections after daily irrigation for one month to reduce bacterial load mechanically., Learning Objective: In a case of purulent pericarditis caused by highly pathogenic methicillin-resistant Staphylococcus aureus resistant to antibiotics and resulting in constrictive pericarditis, it was possible to perform pericardial fenestration in the chronic phase, while mitigating the risk of fatal secondary infections, by controlling the inflammation through daily irrigation for a long time to reduce the bacterial load mechanically., Competing Interests: The authors declare that there is no conflict of interest., (© 2024 Japanese College of Cardiology. Published by Elsevier Ltd.)

Aims: Previous studies have shown that proteinuria is independently associated with the incidence of atrial fibrillation (AF), and is also associated with the incidence of cardiovascular events such as stroke and thromboembolism in patients with AF. However, the association of proteinuria with heart failure (HF) events in patients with AF remains unclear., Methods and Results: The Fushimi AF Registry is a community-based prospective study of patients with AF. Of the entire cohort of 4489 patients, 2164 patients had available data of proteinuria. We compared the clinical background and outcomes between patients with proteinuria (n = 606, 28.0%) and those without (n = 1558, 72.0%). Patients with proteinuria were older and had a higher prevalence of major co-morbidities. During the median follow-up of 5.0 years, the incidence rates of HF events (composite of cardiac death or HF hospitalization) were higher in patients with proteinuria than those without (4.1% vs. 2.1% person-year, P < 0.01). Multivariate analyses revealed that proteinuria was an independent risk factor of the incidence of HF events [adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.13-1.74]. This association was consistent among the various subgroups, except for the age subgroup in which there was a significant interaction (P < 0.01) between younger (<75 years) (unadjusted HR: 3.03, 95% CI: 2.12-4.34) and older (≥75 years) patients (unadjusted HR: 1.59, 95% CI: 1.23-2.05)., Conclusion: Our community-based large prospective cohort suggests that proteinuria is independently associated with the incidence of HF events in Japanese patients with AF., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)