Publications by authors named "Kazuhiro Yamamoto"

461 Publications

Induction of Cross-resistance to ABCB1 Substrates in Venetoclax-resistant Human Leukemia HL60 Cells.

Anticancer Res 2021 Sep 1;41(9):4239-4248. Epub 2021 Sep 1.

Department of Pharmaceutics, Kobe University Graduate School of Medicine, Kobe, Japan.

Background/aim: Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs.

Materials And Methods: Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells.

Results: HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax.

Conclusion: HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.
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http://dx.doi.org/10.21873/anticanres.15228DOI Listing
September 2021

Performance of the HFPEF and the HFA-PEFF scores for the diagnosis of heart failure with preserved ejection fraction in Japanese patients: A report from the Japanese multicenter registry.

Int J Cardiol 2021 Nov 5;342:43-48. Epub 2021 Aug 5.

Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.

Background: Diagnosing heart failure with preserved ejection fraction (HFpEF) is challenging. Although the HFPEF score and HFA-PEFF algorithm have been proposed for diagnosing HFpEF, previous validation studies were conducted in stable chronic heart failure (HF). Moreover, information on their applicability in the Asian population is limited. We sought to investigate these scores' diagnostic performance for HFpEF in Japanese patients recently hospitalized due to acute decompensated HF.

Methods: We examined patients with HFpEF recently hospitalized with acute decompensated HF from a nationwide HFpEF-specific multicenter registry (HFpEF group) and control patients who underwent echocardiography to investigate the cause of dyspnea in our hospital (Non-HFpEF group).

Results: The studied population included 372 patients (194 HFpEF group and 178 Non-HFpEF group; HFpEF prevalence, 52%). A high HFPEF score (6-9 points) could diagnose HFpEF with a high specificity of 97% and a positive predictive value (PPV) of 94%, and a low HFPEF score (0-1 point) could rule out HFpEF with a high sensitivity of 97% and a negative predictive value (NPV) of 93%. HFpEF could be diagnosed with a high HFA-PEFF score (5-6 points) (specificity, 84%; PPV, 82%) or ruled out with a low HFA-PEFF score (0-1 point) (sensitivity, 99%; NPV, 89%). The HFPEF score was significantly superior to the HFA-PEFF score in diagnostic accuracy (area under the curve: 0.89 vs. 0.82, respectively, p = 0.004).

Conclusions: The HFPEF and the HFA-PEFF scores had acceptable diagnostic accuracy in diagnosing HFpEF in Japanese patients.
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http://dx.doi.org/10.1016/j.ijcard.2021.08.001DOI Listing
November 2021

Long-term results of percutaneous transluminal coronary balloon angioplasty in Kawasaki disease.

Cardiol Young 2021 Jul 23:1-3. Epub 2021 Jul 23.

Department of Cardiovascular Medicine, Endocrinology and Metabolism, Tottori University, Yonago, Japan.

We report the long-term results of percutaneous transluminal coronary balloon angioplasty for early appearing localised stenosis of the left anterior descending artery caused by Kawasaki disease in two 2-year-olds. One patient had 50% restenosis and newly appearing aneurysm at 21-year-old, and the other had no restenosis at 16-year-old. They had no symptoms or cardiac events for 20 years. It is useful in the early localised stenosis without aneurysm.
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http://dx.doi.org/10.1017/S1047951121002778DOI Listing
July 2021

Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis.

FEBS J 2021 Jul 16. Epub 2021 Jul 16.

Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, UK.

Matrix metalloproteinase-13 (MMP-13) is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase (NE) is a well-described proteoglycan-degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated pro-MMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at MKKPR, ultimately resulting in the fully active form with the neo-N terminus of YNVFP. Mole-per-mole, activation was more potent than by MMP-3, a classical collagenase activator. Elastase was detectable in human OA synovial fluid and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, (AAT) alpha-1 antitrypsin (gene name SERPINA1), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of pro-MMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.
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http://dx.doi.org/10.1111/febs.16127DOI Listing
July 2021

Impact of delayed hyperenhancement obtained by non-contrast computed tomography following coronary angiography in patients undergoing extracorporeal cardiopulmonary resuscitation.

Resusc Plus 2020 Dec 28;4:100028. Epub 2020 Sep 28.

Department of Cardiovascular Medicine and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.

Background: Extracorporeal cardiopulmonary resuscitation (ECPR) has the potential to improve outcomes in patients with refractory cardiac arrest. However, the outcome is difficult to predict on admission. Recent reports have described early evaluation of myocardial damage in patients with acute myocardial infarction by detecting delayed enhancement in non-contrast computed tomography (CT) following coronary angiography (CAG). We investigated the impact of delayed hyperenhancement obtained by non-contrast CT following CAG in patients with ischaemic and non-ischaemic cardiovascular diseases who underwent ECPR for refractory cardiac arrest.

Methods: Forty-two patients who underwent ECPR, CAG, and postprocedural CT for refractory cardiac arrest in our institute were retrospectively enrolled. Two blinded readers independently and semi-quantitatively judged whether hyperenhancement was present or absent in non-contrast axial CT images following CAG. We evaluated the relationship between in-hospital death and delayed hyperenhancement.

Results: The identification of delayed hyperenhancement was highly consistent between the two readers (kappa ​= ​0.71). The survival rate was 21.4% in this cohort. The only significant difference between the survival group and in-hospital death group was the presence of delayed hyperenhancement, which was detected only in the in-hospital death group (p ​= ​0.03). The prevalence of cardiac death was higher in patients with than without delayed hyperenhancement. Delayed hyperenhancement was observed even in areas perfused by non-obstructive coronary arteries.

Conclusions: Delayed hyperenhancement of the left ventricular wall on non-contrast CT imaging following CAG might help to predict in-hospital death in patients undergoing ECPR for refractory cardiac arrest.
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http://dx.doi.org/10.1016/j.resplu.2020.100028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244388PMC
December 2020

Constraints on Cosmic Strings Using Data from the Third Advanced LIGO-Virgo Observing Run.

Phys Rev Lett 2021 Jun;126(24):241102

SUPA, University of Strathclyde, Glasgow G1 1XQ, United Kingdom.

We search for gravitational-wave signals produced by cosmic strings in the Advanced LIGO and Virgo full O3 dataset. Search results are presented for gravitational waves produced by cosmic string loop features such as cusps, kinks, and, for the first time, kink-kink collisions. A template-based search for short-duration transient signals does not yield a detection. We also use the stochastic gravitational-wave background energy density upper limits derived from the O3 data to constrain the cosmic string tension Gμ as a function of the number of kinks, or the number of cusps, for two cosmic string loop distribution models. Additionally, we develop and test a third model that interpolates between these two models. Our results improve upon the previous LIGO-Virgo constraints on Gμ by 1 to 2 orders of magnitude depending on the model that is tested. In particular, for the one-loop distribution model, we set the most competitive constraints to date: Gμ≲4×10^{-15}. In the case of cosmic strings formed at the end of inflation in the context of grand unified theories, these results challenge simple inflationary models.
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http://dx.doi.org/10.1103/PhysRevLett.126.241102DOI Listing
June 2021

Potentially harmful excipients in neonatal medications: a multicenter nationwide observational study in Japan.

J Pharm Health Care Sci 2021 Jul 1;7(1):23. Epub 2021 Jul 1.

Department of Hospital Pharmacy, Nagoya University Hospital, Nagoya-shi, Aichi, Japan.

Background: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted.

Methods: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE.

Results: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified.

Conclusions: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.
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http://dx.doi.org/10.1186/s40780-021-00208-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246663PMC
July 2021

Development of selective protease inhibitors via engineering of the bait region of human α-macroglobulin.

J Biol Chem 2021 07 15;297(1):100879. Epub 2021 Jun 15.

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark. Electronic address:

Human α-macroglobulin (A2M) is an abundant protease inhibitor in plasma, which regulates many proteolytic processes and is involved in innate immunity. A2M's unique protease-trapping mechanism of inhibition is initiated when a protease cleaves within the exposed and highly susceptible "bait region." As the wild-type bait region is permissive to cleavage by most human proteases, A2M is accordingly a broad-spectrum protease inhibitor. In this study, we extensively modified the bait region in order to identify any potential functionally important elements in the bait region sequence and to engineer A2M proteins with restrictive bait regions, which more selectively inhibit a target protease. A2M in which the bait region was entirely replaced by glycine-serine repeats remained fully functional and was not cleaved by any tested protease. Therefore, this bait region was designated as the "tabula rasa" bait region and used as the starting point for further bait region engineering. Cleavage of the tabula rasa bait region by specific proteases was conveyed by the insertion of appropriate substrate sequences, e.g., basic residues for trypsin. Screening and optimization of tabula rasa bait regions incorporating matrix metalloprotease 2 (MMP2) substrate sequences produced an A2M that was specifically cleaved by MMPs and inhibited MMP2 cleavage activity as efficiently as wild-type A2M. We propose that this approach can be used to develop A2M-based protease inhibitors, which selectively inhibit target proteases, which might be applied toward the clinical inhibition of dysregulated proteolysis as occurs in arthritis and many types of cancer.
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http://dx.doi.org/10.1016/j.jbc.2021.100879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267569PMC
July 2021

Child ego state and self-care behavior change in heart failure patients.

J Cardiol 2021 Oct 2;78(4):294-300. Epub 2021 Jun 2.

Department of Cardiovascular Medicine and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, Yonago, Japan.

Background: The psychological characteristics of ego functions interfere with self-care behavior in several diseases. However, the effect of ego functions on self-care behavior after education in heart failure (HF) remains unclear.

Methods: Seventy-one HF patients were enrolled. Patients' scores on the Japanese version of the European Heart Failure Self-care Behaviour Scale (EHFScBS) were measured before and after the HF intervention, and the rate of change was used as an indicator of educational effectiveness. The Tokyo University Egogram New Ver. II was used to assess five types of ego state functions: Critical parent, Nurturing parent, Adult, Free Child, and Adapted Child (AC).

Results: A comparison of the five ego states showed that AC scores were significantly lower than those of the other ego states (p < 0.01). Total EHFScBS scores significantly decreased from 33 (26-39) to 16 (14-20) (p < 0.01) after the HF education, and the median rates of change in EHFScBS was -46.2%. Patients with a lower rate of change in EHFScBS were more likely to have low AC scores, as characterized by a lack of compliance and coordination, and were less likely to receive higher education (all p < 0.05). Even after adjustment for covariates, low AC scores were independently associated with low rate of change in EHFScBS (p < 0.01).

Conclusions: Educational behavior change for self-care is less effective in HF patients with an ego state with low AC.
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http://dx.doi.org/10.1016/j.jjcc.2021.05.006DOI Listing
October 2021

Sleep Disorder and Heart Failure with Preserved Ejection Fraction.

Heart Fail Clin 2021 Jul;17(3):369-376

Department of Cardiovascular Medicine, and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, Japan.

It is generally considered that obstructive sleep apnea is a potential cause of heart failure (HF), and insomnia and central sleep apnea are results of HF. However, the number of reports describing the bidirectional relationship between sleep disorder and HF has increased. Sleep disorder may contribute to left ventricular diastolic dysfunction via left atrial overload, left ventricular remodeling, pulmonary hypertension, and atrial fibrillation, which lead to HF with preserved left ventricular ejection fraction. Overnight rostral fluid shift and lung congestion may lead to airflow obstruction in the upper pharynx and stimulate pulmonary irritant receptors, which induce hyperventilation and sleep disorder.
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http://dx.doi.org/10.1016/j.hfc.2021.02.004DOI Listing
July 2021

A successful case of varix of the left gastroepiploic vein preoperatively diagnosed by 3D-CT angiography and resected by laparoscopy: A case report.

Medicine (Baltimore) 2021 Apr;100(16):e25347

Department of General and Gastroenterological Surgery.

Introduction: Gastric varices can be present in up to 20% of patients with portal hypertension. However, a varix of the left gastroepiploic vein (LGV) is extremely rare. Surgery is required if bleeding occurs; thus, precise diagnosis is crucial. We present a successful case of preoperative diagnosis intraabdominal varix of the LGV using three-dimensional-computed tomography angiography (3D-CTA) followed by laparoscopic resection. This is the first report of a case with variant LGV. Our study demonstrates the efficacies of 3D-CTA and laparoscopic surgery for the diagnosis and safe resection of the intraabdominal varix, respectively.

Patient Concerns: A 74-year-old woman was referred to our department with a tumor in the abdominal cavity. On physical examination, no lumps were palpable in the upper abdomen.

Diagnosis: The enhanced CT was revealed that the tumor was not enhanced in the early phase, but in the equilibrium phase. Moreover, 3D-CTA clearly revealed that the tumor was being supplied by the LGV. Thus, it was diagnosed as a variant of the LGV.

Interventions: Surgical resection was performed laparoscopically as per the guidance of preoperative 3D-CTA findings. During surgery, a dark tumor was found along the gastroepiploic vessels, supplied by the LGV. The tumor was resected safely based on the preoperative information.

Outcomes: Histopathological examination of the tumor showed accumulation of various vessels, but no malignant cells. Therefore, we made a final diagnosis of the tumor as an LGV varix. For follow-up, an annual CT examination was performed and after 3 years postoperation, no recurrence was observed.

Conclusions: In the present case, we have achieved a successful preoperative diagnosis using 3D-CTA, and resection was safely accomplished using laparoscopy guided by preoperative anatomical information. This is the first report of an LGV variant. Appropriate management is crucial because bleeding is a catastrophic event. Therefore, imaging procedures such as 3D-CTA for diagnosis, followed by safe resection by laparoscopic surgery, are effective tools for the treatment of epiploic vein varices.
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http://dx.doi.org/10.1097/MD.0000000000025347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078386PMC
April 2021

Impact of Inadequate Calorie Intake on Mortality and Hospitalization in Stable Patients with Chronic Heart Failure.

Nutrients 2021 Mar 8;13(3). Epub 2021 Mar 8.

School of Nursing, Kitasato University, Sagamihara 252-0373, Japan.

Malnutrition is highly prevalent in patients with heart failure (HF), but the precise impact of dietary energy deficiency on HF patients' clinical outcomes is not known. We investigated the associations between inadequate calorie intake and adverse clinical events in 145 stable outpatients with chronic HF who had a history of hospitalization due to worsening HF. To assess the patients' dietary pattern, we used a brief self-administered diet-history questionnaire (BDHQ). Inadequate calorie intake was defined as <60% of the estimated energy requirement. In the total chronic HF cohort, the median calorie intake was 1628 kcal/day. Forty-four patients (30%) were identified as having an inadequate calorie intake. A Kaplan-Meier analysis revealed that the patients with inadequate calorie intake had significantly worse clinical outcomes including all-cause death and HF-related hospitalization during the 1-year follow-up period versus those with adequate calorie intake (20% vs. 5%, < 0.01). A multivariate logistic regression analysis showed that inadequate calorie intake was an independent predictor of adverse clinical events after adjustment for various factors that may influence patients' calorie intake. Among patients with chronic HF, inadequate calorie intake was associated with an increased risk of all-cause mortality and rehospitalization due to worsening HF. However, our results are preliminary and larger studies with direct measurements of dietary calorie intake and total energy expenditure are needed to clarify the intrinsic nature of this relationship.
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http://dx.doi.org/10.3390/nu13030874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998469PMC
March 2021

Trimethylamine N-oxide and outcomes in patients hospitalized with acute heart failure and preserved ejection fraction.

ESC Heart Fail 2021 06 18;8(3):2103-2110. Epub 2021 Mar 18.

Department of Cardiovascular Medicine and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, 36-1 Nishicho, Yonago, 683-8504, Japan.

Aims: Trimethylamine N-oxide (TMAO) is a metabolite derived from the gut microbiota. Elevated TMAO levels are associated with a poor prognosis in patients with heart failure with reduced ejection fraction. However, the prognostic effect of elevated TMAO levels on heart failure with preserved ejection fraction (HFpEF) remains unclear.

Methods And Results: We consecutively enrolled 146 patients who were hospitalized and discharged from Tottori University Hospital with the primary diagnosis of HFpEF (ejection fraction ≥ 50%). High TMAO levels were defined as those greater than the median value in the patients (20.37 μmol/L). Patients with high TMAO levels had a significantly higher prevalence of prior hospitalization for heart failure and severe renal dysfunction than those with low TMAO levels. They also had a significantly higher acylcarnitine to free carnitine ratio than those with low TMAO levels, which indicated abnormal fatty acid metabolism and relative carnitine deficiency. After adjustment for differences in the patients' background in multivariate analysis, high TMAO levels remained independently associated with a high incidence of the composite endpoints of death due to cardiac causes and hospitalization for heart failure (adjusted hazard ratio, 1.91; 95% confidence interval, 1.01 to 3.62; P < 0.05). There was a significant interaction between TMAO and nutritional status on the primary outcome, and the prognostic effect of TMAO was enhanced in patients with malnutrition.

Conclusions: Elevated TMAO levels at discharge are associated with an increased risk of post-discharge cardiac events in patients with HFpEF, especially those with the complication of malnutrition.
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http://dx.doi.org/10.1002/ehf2.13290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120352PMC
June 2021

Efficacy and Safety of Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction - Results From the PARALLEL-HF Study.

Circ J 2021 04 16;85(5):584-594. Epub 2021 Mar 16.

Novartis Pharmaceutical Corporation.

Background: In the Prospective Comparison of angiotensin receptor neprilysin inhibitor (ARNI) With ACEi to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study, treatment with sacubitril/valsartan reduced the primary outcome of cardiovascular (CV) death and heart failure (HF) hospitalization compared with enalapril in patients with chronic HF and reduced ejection fraction (HFrEF). A prospective randomized trial was conducted to assess the efficacy and safety of sacubitril/valsartan in Japanese HFrEF patients.Methods and Results:In the Prospective comparison of ARNI with ACEi to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients (PARALLEL-HF) study, 225 Japanese HFrEF patients (New York Heart Association [NYHA] class II-IV, left ventricular ejection fraction [LVEF] ≤35%) were randomized (1 : 1) to receive sacubitril/valsartan 200 mg bid or enalapril 10 mg bid. Over a median follow up of 33.9 months, no significant between-group difference was observed for the primary composite outcome of CV death and HF hospitalization (HR 1.09; 95% CI 0.65-1.82; P=0.6260). Early and sustained reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline were observed with sacubitril/valsartan compared with enalapril (between-group difference: Week 2: 25.7%, P<0.01; Month 6: 18.9%, P=0.01, favoring sacubitril/valsartan). There was no significant difference in the changes in NYHA class and Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score at Week 8 and Month 6. Sacubitril/valsartan was well tolerated with fewer study drug discontinuations due to adverse events, although the sacubitril/valsartan group had a higher proportion of patients with hypotension.

Conclusions: In Japanese patients with HFrEF, there was no difference in reduction in the risk of CV death or HF hospitalization between sacubitril/valsartan and enalapril, and sacubitril/valsartan was safe and well tolerated.
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http://dx.doi.org/10.1253/circj.CJ-20-0854DOI Listing
April 2021

Esm1 and Stc1 as Angiogenic Factors Responsible for Protective Actions of Adipose-Derived Stem Cell Sheets on Chronic Heart Failure After Rat Myocardial Infarction.

Circ J 2021 04 12;85(5):657-666. Epub 2021 Mar 12.

Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science.

Background: Although adipose-derived stem cell (ADSC) sheets improve the cardiac function after myocardial infarction (MI), underlying mechanisms remain to be elucidated. The aim of this study was to determine the fate of transplanted ADSC sheets and candidate angiogenic factors released from ADSCs for their cardiac protective actions.Methods and Results:MI was induced by ligation of the left anterior descending coronary artery. Sheets of transgenic (Tg)-ADSCs expressing green fluorescence protein (GFP) and luciferase or wild-type (WT)-ADSCs were transplanted 1 week after MI. Both WT- and Tg-ADSC sheets improved cardiac functions evaluated by echocardiography at 3 and 5 weeks after MI. Histological examination at 5 weeks after MI demonstrated that either sheet suppressed fibrosis and increased vasculogenesis. Luciferase signals from Tg-ADSC sheets were detected at 1 and 2 weeks, but not at 4 weeks, after transplantation. RNA sequencing of PKH (yellow-orange fluorescent dye with long aliphatic tails)-labeled Tg-ADSCs identified mRNAs of 4 molecules related to angiogenesis, including those of Esm1 and Stc1 that increased under hypoxia. Administration of Esm1 or Stc1 promoted tube formation by human umbilical vein endothelial cells.

Conclusions: ADSC sheets improved cardiac contractile functions after MI by suppressing cardiac fibrosis and enhancing neovascularization. Transplanted ADSCs existed for >2 weeks on MI hearts and produced the angiogenic factors Esm1 and Stc1, which may improve cardiac functions after MI.
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http://dx.doi.org/10.1253/circj.CJ-20-0877DOI Listing
April 2021

Cost analysis of transcatheter versus surgical aortic valve replacement in octogenarians: analysis from a single Japanese center.

Heart Vessels 2021 Oct 12;36(10):1558-1565. Epub 2021 Mar 12.

Division of Cardiovascular Surgery, Tottori University School of Medicine, 36-1 Nishi-cho, Yonago, Tottori, 683-8504, Japan.

Transcatheter aortic valve replacement (TAVR) has revolutionized the prognosis of intermediate- or high-risk patients with severe aortic stenosis, particularly among older adults. However, in possible candidates for surgical aortic valve replacement (SAVR), the implantation of expensive prostheses may be questionable in an era when healthcare costs are becoming a major concern. In this retrospective analysis of a single Japanese center, we focused on patients aged over 80 years; the objectives of this study were: (1) to compare TAVR and SAVR in terms of total hospitalization costs and (2) to describe the itemized cost of TAVR and SAVR to identify patients aged over 80 years in whom TAVR or SAVR would be cost-effective. A total of 146 patients aged over 80 years who underwent TAVR or SAVR for severe aortic stenosis were included. These patients were divided into a high-risk group (Society of Thoracic Surgeons [STS] mortality score > 8%; 36: TAVR and 12: SAVR) with 48 patients and a non-high-risk group (STS mortality score < 8%; 45: TAVR and 53 SAVR) with 98 patients. No 30-day mortality was observed in either group. In both groups, postoperative intensive care unit stay and hospital stay were longer with SAVR than with TAVR. In the non-high-risk group, the total cost was comparable for TAVR and SAVR; however, in the high-risk group, the total cost was significantly higher with SAVR than that with TAVR. A breakdown analysis of the total cost in the high-risk group showed both pre- and postoperative costs to be significantly higher with SAVR than with TAVR; however, operative costs were higher with TAVR. Up to 3 years, the overall survival in both groups did not significantly differ between TAVR and SAVR. Our findings suggest that from the perspective of total medical costs, TAVR is more suitable than SAVR for high-risk older adults.
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http://dx.doi.org/10.1007/s00380-021-01826-xDOI Listing
October 2021

Effect of the COVID-19 Pandemic on Acute Respiratory Care of Hypoxemic Patients With Acute Heart Failure in Japan - A Cross-Sectional Study.

Circ Rep 2020 Aug 13;2(9):499-506. Epub 2020 Aug 13.

Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University Fukuoka Japan.

The effect of the COVID-19 pandemic on the respiratory management strategy with regard to the use of non-invasive positive pressure ventilation (NPPV) and high-flow nasal cannula (HFNC) in patients with acute heart failure (AHF) in Japan is unclear. This cross-sectional study used a self-reported online questionnaire, with responses from 174 institutions across Japan. More than 60% of institutions responded that the treatment of AHF patients requiring respiratory management became fairly or very difficult during the COVID-19 pandemic than earlier, with institutions in alert areas considering such treatment significantly more difficult than those in non-alert areas (P=0.004). Overall, 61.7% and 58.8% of institutions changed their indications for NPPV and HFNC, respectively. Significantly more institutions in the alert area changed their practices for the use of NPPV and HFNC during the COVID-19 pandemic (P=0.004 and P=0.002, respectively). When there was insufficient time or information to determine whether AHF patients may have concomitant COVID-19, institutions in alert areas were significantly more likely to refrain from using NPPV and HFNC than institutions in non-alert areas. The COVID-19 pandemic has compelled healthcare providers to change the respiratory management of AHF, especially in alert areas.
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http://dx.doi.org/10.1253/circrep.CR-20-0081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819655PMC
August 2020

Evidence for Urate Uptake Through Monocarboxylate Transporter 9 Expressed in Mammalian Cells and Its Enhancement by Heat Shock.

Circ Rep 2020 Jul 2;2(8):425-432. Epub 2020 Jul 2.

Department of Genetic Medicine and Regenerative Therapeutics, Tottori University Graduate School of Medical Science Tottori Japan.

Monocarboxylate transporter 9 (MCT9), an orphan transporter member of the solute carrier family 16 (SLC16), possibly reabsorbs uric acid in the renal tubule and has been suggested by genome-wide association studies to be involved in the development of hyperuricemia and gout. In this study we investigated the mechanisms regulating the expression of human (h) MCT9, its degradation, and physiological functions. hMCT9-FLAG was stably expressed in HEK293 cells and its degradation, intracellular localization, and urate uptake activities were assessed by pulse-chase analysis, immunofluorescence, and [C]-urate uptake experiments, respectively. hMCT9-FLAG was localized on the plasma membrane as well as in the endoplasmic reticulum and Golgi apparatus. The proteasome inhibitors MG132 and lactacystine increased levels of hMCT9-FLAG protein expression with enhanced ubiquitination, prolonged their half-life, and decreased [C]-urate uptake. [C]-urate uptake was increased by both heat shock (HS) and the HS protein inducer geranylgeranylacetone (GGA). Both HS and GGA restored the [C]-urate uptake impaired by MG132. hMCT9 does transport urate and is degraded by a proteasome, inhibition of which reduces hMCT9 expression on the cell membrane and urate uptake. HS enhanced urate uptake through hMCT9.
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http://dx.doi.org/10.1253/circrep.CR-20-0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819574PMC
July 2020

Universal Definition and Classification of Heart Failure: A Report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure.

J Card Fail 2021 Mar 1. Epub 2021 Mar 1.

In this document, we propose a universal definition of heart failure (HF) as the following: HF is a clinical syndrome with symptoms and or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and or objective evidence of pulmonary or systemic congestion. We propose revised stages of HF as follows. At-risk for HF (Stage A), for patients at risk for HF but without current or prior symptoms or signs of HF and without structural or biomarkers evidence of heart disease. Pre-HF (stage B), for patients without current or prior symptoms or signs of HF, but evidence of structural heart disease or abnormal cardiac function, or elevated natriuretic peptide levels. HF (Stage C), for patients with current or prior symptoms and/or signs of HF caused by a structural and/or functional cardiac abnormality. Advanced HF (Stage D), for patients with severe symptoms and/or signs of HF at rest, recurrent hospitalizations despite guideline-directed management and therapy (GDMT), refractory or intolerant to GDMT, requiring advanced therapies such as consideration for transplant, mechanical circulatory support, or palliative care. Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). The classification includes HF with reduced EF (HFrEF): HF with an LVEF of ≤40%; HF with mildly reduced EF (HFmrEF): HF with an LVEF of 41% to 49%; HF with preserved EF (HFpEF): HF with an LVEF of ≥50%; and HF with improved EF (HFimpEF): HF with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.
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http://dx.doi.org/10.1016/j.cardfail.2021.01.022DOI Listing
March 2021

Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association.

Eur J Heart Fail 2021 03 3;23(3):352-380. Epub 2021 Mar 3.

In this document, we propose a universal definition of heart failure (HF) as a clinical syndrome with symptoms and/or signs caused by a structural and/or functional cardiac abnormality and corroborated by elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion. We also propose revised stages of HF as: At risk for HF (Stage A), Pre-HF (Stage B), Symptomatic HF (Stage C) and Advanced HF (Stage D). Finally, we propose a new and revised classification of HF according to left ventricular ejection fraction (LVEF). This includes HF with reduced ejection fraction (HFrEF): symptomatic HF with LVEF ≤40%; HF with mildly reduced ejection fraction (HFmrEF): symptomatic HF with LVEF 41-49%; HF with preserved ejection fraction (HFpEF): symptomatic HF with LVEF ≥50%; and HF with improved ejection fraction (HFimpEF): symptomatic HF with a baseline LVEF ≤40%, a ≥10 point increase from baseline LVEF, and a second measurement of LVEF > 40%.
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http://dx.doi.org/10.1002/ejhf.2115DOI Listing
March 2021

After four years in the role of Editor-in-Chief.

J Cardiol Cases 2021 Jan 22;23(1). Epub 2020 Oct 22.

Department of Cardiovascular Medicine, and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, Yonago, Japan.

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http://dx.doi.org/10.1016/j.jccase.2020.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783670PMC
January 2021

Umami taste disorder is a novel predictor of obesity.

Hypertens Res 2021 05 7;44(5):595-597. Epub 2020 Dec 7.

Department of Genetic Medicine and Regenerative Therapeutics, Institute of Regenerative Medicine and Biofunction, Tottori University Graduate School of Medical Science, Tottori, Japan.

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http://dx.doi.org/10.1038/s41440-020-00588-9DOI Listing
May 2021

Erratum for Ikeda et al., "Pemafibrate Dramatically Ameliorated the Values of Liver Function Tests and Fibrosis Marker in Patients with Non-Alcoholic Fatty Liver Disease".

Yonago Acta Med 2020 Nov 24;63(4):385. Epub 2020 Nov 24.

Division of Medicine and Clinical Science, Department of Gastroenterology and Nephrology, School of Medicine, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan and.

[This corrects the article DOI: 10.33160/yam.2020.08.009.].
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http://dx.doi.org/10.33160/yam.2020.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683890PMC
November 2020

Sunitinib decreases the expression of KRT6A and SERPINB1 in 3D human epidermal models.

Exp Dermatol 2021 Mar 17;30(3):337-346. Epub 2020 Nov 17.

Department of Pharmacy, Kobe University Hospital, Kobe, Japan.

Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3β by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.
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http://dx.doi.org/10.1111/exd.14230DOI Listing
March 2021

l-Carnitine supplementation in heart failure patients with preserved ejection fraction; a pilot study.

Geriatr Gerontol Int 2020 Dec 13;20(12):1244-1245. Epub 2020 Oct 13.

Department of Cardiovascular Medicine and Endocrinology and Metabolism, Faculty of Medicine, Tottori University, Yonago, Japan.

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http://dx.doi.org/10.1111/ggi.14060DOI Listing
December 2020

Underwater endoscopic observation and mucosal resection for gastric protruding polyps.

Endosc Int Open 2020 Oct 7;8(10):E1458-E1459. Epub 2020 Oct 7.

Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.

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http://dx.doi.org/10.1055/a-1229-4280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541183PMC
October 2020

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA.

Living Rev Relativ 2020 28;23(1). Epub 2020 Sep 28.

LIGO, California Institute of Technology, Pasadena, CA 91125 USA.

We present our current best estimate of the plausible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next several years, with the intention of providing information to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals for the third (O3), fourth (O4) and fifth observing (O5) runs, including the planned upgrades of the Advanced LIGO and Advanced Virgo detectors. We study the capability of the network to determine the sky location of the source for gravitational-wave signals from the inspiral of binary systems of compact objects, that is binary neutron star, neutron star-black hole, and binary black hole systems. The ability to localize the sources is given as a sky-area probability, luminosity distance, and comoving volume. The median sky localization area (90% credible region) is expected to be a few hundreds of square degrees for all types of binary systems during O3 with the Advanced LIGO and Virgo (HLV) network. The median sky localization area will improve to a few tens of square degrees during O4 with the Advanced LIGO, Virgo, and KAGRA (HLVK) network. During O3, the median localization volume (90% credible region) is expected to be on the order of for binary neutron star, neutron star-black hole, and binary black hole systems, respectively. The localization volume in O4 is expected to be about a factor two smaller than in O3. We predict a detection count of ( ) for binary neutron star mergers, of ( ) for neutron star-black hole mergers, and ( ) for binary black hole mergers in a one-calendar-year observing run of the HLV network during O3 (HLVK network during O4). We evaluate sensitivity and localization expectations for unmodeled signal searches, including the search for intermediate mass black hole binary mergers.
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http://dx.doi.org/10.1007/s41114-020-00026-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7520625PMC
September 2020
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