Publications by authors named "Hiromi Rakugi"

520 Publications

Angiotensin receptor-neprilysin inhibitors: Comprehensive review and implications in hypertension treatment.

Hypertens Res 2021 Jul 21. Epub 2021 Jul 21.

The Department of Geriatric and General Medicine, Osaka university Graduate School of Medicine, Suita, Osaka, Japan.

Angiotensin receptor-neprilysin inhibitors (ARNIs) are a new class of cardiovascular agents characterized by their dual action on the major regulators of the cardiovascular system, including the renin-angiotensin system (RAS) and the natriuretic peptide (NP) system. The apparent clinical benefit of one ARNI, sacubitril/valsartan, as shown in clinical trials, has positioned the drug class as a first-line therapy in patients with heart failure, particularly with reduced ejection fraction. Accumulating evidence also suggests that sacubitril/valsartan is superior to conventional RAS blockers in lowering blood pressure in patients with hypertension. To decide whether to apply an ARNI to treat hypertension clinically, it is important to understand the potential properties of the drug in modulating multiple factors inside and outside the cardiovascular system beyond its effect on reducing peripheral blood pressure. In this context, ARNIs are distinct from preexisting antihypertensive medications in terms of the multiple actions of NPs in various organs and the pharmacological potential of neprilysin inhibitors to modulate multiple cardiac and noncardiac peptides. In particular, analysis of the clinical trials of sacubitril/valsartan implies that ARNIs can provide additional clinical benefits independent of their original purpose, including alleviation of glycemic control and renal impairment in patients with heart failure. Understanding the potential mechanisms of action of ARNIs will help interpret the relevance of their additional benefits beyond lowering blood pressure in hypertension. This review summarizes the comprehensive clinical evidence and relevance of ARNIs by specifically focusing on the potential properties of this new drug class in treating patients with hypertension.
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http://dx.doi.org/10.1038/s41440-021-00706-1DOI Listing
July 2021

Periodontal inflamed surface area is associated with hs-CRP in septuagenarian Japanese adults in cross-sectional findings from the SONIC study.

Sci Rep 2021 Jul 14;11(1):14436. Epub 2021 Jul 14.

Department of Periodontology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Periodontal disease is a chronic inflammatory condition that affects various peripheral organs. The periodontal inflamed surface area (PISA) quantifies periodontitis severity and the spread of inflammatory wounds. This study aimed to investigate the association between PISA and high-sensitivity C-reactive protein (hs-CRP), a systemic inflammation marker. This study included 250 community-dwelling septuagenarians (69-71 years). We collected information on their medical (e.g., diabetes and dyslipidemia) and dental examinations (e.g., measurement of the probing pocket depth). Generalized linear model analysis was used to explore the association between PISA and hs-CRP levels. There was a significant difference in hs-CRP levels between groups with PISA ≥ 500 and < 500 (p = 0.017). Moreover, the generalized linear model analysis revealed a significant association between PISA and hs-CRP levels (risk ratio = 1.77; p = 0.033) even after adjusting other factors. Further, we found a correlation between PISA and hs-CRP (Spearman's rank correlation coefficient, rs = 0.181; p = 0.023). Our findings suggest that PISA is an effective index for estimating the effect of periodontitis on the whole body, enabling medical-dental cooperation.
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http://dx.doi.org/10.1038/s41598-021-93872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280099PMC
July 2021

The association between longevity associated FOXO3 allele and heart disease in Septuagenarians and Octogenarians: The SONIC study.

J Gerontol A Biol Sci Med Sci 2021 Jul 13. Epub 2021 Jul 13.

Department of Health Promotion System Sciences, Division of Health Sciences, Graduate School of Medicine, Osaka University, Osaka, Japan.

The G allele of FOXO3 gene (Single nucleotide polymorphism - SNP; rs2802292) is strongly associated with human longevity. However, knowledge of the effect of FOXO3 in older populations, men or women, with heart disease is limited. This cross-sectional study in Japan included 1836 older adults in the 70 and 80-year-old groups. DNA samples isolated from buffy coat samples of peripheral blood were used to genotype FOXO3 (rs2802292). Self-reports were used to obtain heart disease data according to physician diagnosis. Multiple logistic regression was used to test the association by adjusting for the traditional risk factor of heart disease. The prevalence of heart disease in women FOXO3 G allele carriers was higher than non-carriers (16.7 vs. 11.6%, p=.022). The prevalence of coronary heart disease was lower for FOXO3 G carriers in the 70-year-old group for both sexes (men: 9.3 vs. 4.3%, p=.042, and women: 10 vs. 9%, p=.079, respectively). The G allele was negatively associated with heart disease after adjusting for diabetes, hypertension, dyslipidemia, and smoking in men (odds ratio (OR)= 0.70, 95%confidence intervals (CI), 0.49-0.99, p=.046), although the association was weaker after full adjustment. In contrast, women carriers of the FOXO3 G allele showed a positive association with heart disease after total adjustment (OR= 1.49, 95%CI, 1.00-2.21, p=.049). In conclusion, the longevity associated G allele of FOXO3 was observed to have contrasting associations with heart disease prevalence according to sex in older Japanese. To further confirm this association, a longitudinal study and a large sample size will be required.
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http://dx.doi.org/10.1093/gerona/glab204DOI Listing
July 2021

Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging-Related Muscle Weakness in Male Mice.

J Am Heart Assoc 2021 Jul 2;10(13):e021030. Epub 2021 Jul 2.

Department of Geriatric and General Medicine Osaka University Graduate School of Medicine Suita Japan.

Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin-(1-7), respectively, is the primary process that counteracts activation of the canonical renin-angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging-related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild-type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS-associated genes, inflammation-associated genes, and senescence-associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging-associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging-associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.
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http://dx.doi.org/10.1161/JAHA.120.021030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403326PMC
July 2021

Prevention of Acute Lung Injury by a Novel CD14-Inhibitory Receptor Activator of the NF-κB Ligand Peptide in Mice.

Immunohorizons 2021 Jun 15;5(6):438-447. Epub 2021 Jun 15.

Department of Geriatric of General Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.

Although CD14 has been implicated in the initiation of multiple TLR-mediated inflammatory responses to sepsis and sepsis-related acute lung injury (ALI), an inhibitor of CD14, except for neutralizing Abs, has not been developed. A partial peptide, microglial healing peptide 1 with N-terminal acetylation and C-terminal amidation (MHP1-AcN), derived from the receptor activator of the NF-кB ligand, was recently found to inhibit multiple TLR signaling in the macrophages. Therefore, we hypothesized that the inhibitory effect of MHP1-AcN might be through the inhibition of CD14, a common coreceptor for multiple TLRs. In cultured mouse macrophages, MHP1-AcN was shown to bind to CD14 and compete with LPS for competitive inhibition of CD14, resulting in inhibition of TLR4 signaling, including NF-кB and IFN regulatory factor 3 activation and nuclear translocation. In addition to TLR2, TLR4, and TLR7, MHP1-AcN also inhibited TLR3 signaling and DNA-induced, CD14-dependent TLR9 signals; however, CpG oligodeoxynucleotide-induced, CD14-independent TLR9 signals were not inhibited in the mouse macrophages. In sepsis-induced ALI mouse model, MHP1-AcN treatment showed the reduction in the expression of IL-6 and CCL2 in both the serum and lung tissues. IL-6 levels in the bronchoalveolar lavage fluid and pathological score were also decreased by MHP1-AcN. Thus, MHP1-AcN, a novel CD14 inhibitor, could be a promising agent for treating sepsis-induced ALI.
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http://dx.doi.org/10.4049/immunohorizons.2000112DOI Listing
June 2021

Therapeutic vaccine for chronic diseases after the COVID-19 Era.

Hypertens Res 2021 09 8;44(9):1047-1053. Epub 2021 Jun 8.

Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Japan.

There is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.
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http://dx.doi.org/10.1038/s41440-021-00677-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184354PMC
September 2021

A Randomized Trial of Home Blood-Pressure Reduction by Alcohol Guidance during Outpatient Visits: OSAKE study.

Am J Hypertens 2021 May 23. Epub 2021 May 23.

Department of Health Sciences, Osaka University Graduate School of Medicine, Suita, Japan.

Objective: To evaluate the effectiveness of the nurse-led alcohol guidance to control home blood pressure in the morning (HBP) among male patients with hypertension during outpatient visits.

Method: We enrolled 53 male patients with an HBP of ≥ 135/85 mmHg with excessive drinking (alcohol ≥210 g/week or ≥60 g/day habitually) among outpatients in a randomized trial. Patients were assigned to a nurse-led intervention (in which patients were encouraged to reduce their alcohol consumption in addition to the usual treatment every 2 months) or to the control (in which patients were followed by their doctor as usual). The primary outcomes were the mean HBP of 5 consecutive days at 6 months and alcohol consumption.

Results: Twenty-eight and 25 patients were randomized to intervention and control groups, respectively (mean age; 62.7 years old and 64.5, respectively). At baseline, the mean HBP was 143/90 mmHg in the intervention group and 144/88 mmHg in the control group (n.s.). At 6 months, the mean HBP was 131/82 mmHg and 145/87 mmHg, respectively (SBP<0.001, DBP=0.09). An HBP level of less than 135/85 mmHg was achieved among 55.6% of the participants in the intervention group versus 16.7% in the control group (P=0.004). At baseline, the weekly alcohol consumption was 479±353 g in the intervention group and 360±182 g in the control group (n.s.). At 6 months, it was 256±206 g and 413±260 g, respectively (p=0.020).

Conclusions: We confirmed the effectiveness of the nurse-led alcohol guidance to control the HBP in male patients with hypertension during outpatient visits.
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http://dx.doi.org/10.1093/ajh/hpab082DOI Listing
May 2021

Clinical studies on pharmacological treatment of hypertension in Japan.

J Hum Hypertens 2021 May 7. Epub 2021 May 7.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

Differences in the epidemiology and phenotypes of hypertension in Japan compared with Western countries mean that optimal approaches to the pharmacological management of hypertension should be based on local data. Fortunately, there is a large body of evidence from studies conducted in Japanese populations to inform guidelines and treatment decisions. This article highlights treatment recommendations and BP targets for Japanese patients with hypertension, and summarizes key literature supporting these recommendations. The latest version of the Japanese Society of Hypertension (JSH) guidelines is consistent with US and European guidelines in recommending that the general BP target should be <130/80 mmHg for office blood pressure (BP) and <125/75 mmHg for home BP. There is good local evidence to support these targets. The JSH guidelines also strongly recommend that antihypertensive therapy is managed and monitored based on home BP, due to the closer association of this parameter with cardiovascular risk compared with office BP. Japan is a leader in out-of-office BP research, meaning that there is good evidence for the Japanese recommendations. Key features of antihypertensive agents for use in Japanese patients with hypertension include the ability to reduce stroke risk provide antihypertensive efficacy throughout the 24-h dosing period. Calcium channel blockers appear to be particularly effective in Asian populations, and are the most commonly prescribed agents in Japan. Again consistent with international recommendations, antihypertensive therapy should be started with a combination of agents to maximize the chances of achieving target BP.
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http://dx.doi.org/10.1038/s41371-021-00533-4DOI Listing
May 2021

Periostin Short Fragment with Exon 17 via Aberrant Alternative Splicing Is Required for Breast Cancer Growth and Metastasis.

Cells 2021 04 14;10(4). Epub 2021 Apr 14.

Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Background: Periostin (POSTN) is a 93 kDa matrix protein that helps to regulate collagen gene expression in the extracellular matrix. POSTN overexpression is a prognostic factor in malignant cancers; however, some researchers have observed it in the stroma, whereas others have reported it on tumors.

Objective: This study aimed to investigate the function of POSTN on tumors.

Methods And Results: We found that POSTN in cancer cells can be detected by using an antibody against the POSTN C-terminal region exon 17 (Ex17 antibody), but not with an antibody against the POSTN N-terminal region exon 12 (Ex12 antibody) in patients with breast cancer. In a fraction secreted from fibroblasts, LC-MS/MS analysis revealed a short fragment of POSTN of approximately 40 kDa with exon 17. In addition, molecular interaction analysis showed that POSTN with exon 17, but not POSTN without exon 17, bound specifically to wnt3a, and the Ex17 antibody inhibited the binding.

Conclusion: A short fragment of POSTN with exon 17, which originates in the fibroblasts, is transported to cancer cells, whereas POSTN fragments without exon 17 are retained in the stroma. The Ex17 antibody inhibits the binding between POSTN exon 17 and wnt3a.
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http://dx.doi.org/10.3390/cells10040892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070743PMC
April 2021

Disseminated gonococcal infection in a Japanese man with complement 7 deficiency with compound heterozygous variants: A case report.

Medicine (Baltimore) 2021 Apr;100(13):e25265

Department of General Medicine.

Rationale: Complement deficiency are known to be predisposed to disseminated gonococcal infection (DGI). We herein present a case of DGI involving a Japanese man who latently had a complement 7 deficiency with compound heterozygous variants.

Patient Concerns: A previously healthy 51-year-old Japanese man complained of sudden-onset high fever. Physical examination revealed various skin lesions including red papules on his trunk and extremities, an impetigo-like pustule on left forearm, and tendinitis of his right forefinger.

Diagnosis: Blood culture testing detected gram-negative cocci, which was confirmed to be Neisseria gonorrhoeae based on mass spectrometry and a pathogen-specific PCR test.

Interventions: Screening tests for underlying immunocompromised factors uncovered that complement activities (CH50) was undetectable. With a suspicion of a congenital complement deficiency, genetic analysis revealed rare single nucleotide variants in complement 7 (C7), including c.281-1G>T and a novel variant c.1454C>T (p.A485V). CH50 was normally recovered by adding purified human C7 to the patient's serum, supporting that the patient has C7 deficiency with compound heterozygous variants.

Outcomes: Under a diagnosis of DGI, the patient underwent an antibiotic treatment with cefotaxime for a week and was discharged without any sequela.

Lessons: DGI is a rare sexually-transmitted infection that potentially induces systemic complications. Complement immunity usually defeats N. gonorrhoeae and prevents the organism from causing DGI. This case highlighted the importance of suspecting a complement deficiency when a person develops DGI.
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http://dx.doi.org/10.1097/MD.0000000000025265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021336PMC
April 2021

Age-stratified comparison of clinical outcomes between medical and surgical treatments in patients with unilateral primary aldosteronism.

Sci Rep 2021 03 25;11(1):6925. Epub 2021 Mar 25.

Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.

Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.
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http://dx.doi.org/10.1038/s41598-021-86290-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994572PMC
March 2021

Impact of occlusal force on decline in body mass index among older Japanese adults: Finding from the SONIC study.

J Am Geriatr Soc 2021 Jul 24;69(7):1956-1963. Epub 2021 Mar 24.

Department of Prosthodontics, Gerodontology and Oral Rehabilitation, Osaka University Graduate School of Dentistry, Osaka, Japan.

Objectives: To determine any independent influence of occlusal force and of number of natural teeth on decline in body mass index (BMI) among older Japanese adults.

Design: Longitudinal study over a 3- to 6-year period.

Setting: Urban and rural area in Japan.

Participants: Independently living Japanese adults aged 69-71 years and 79-81 years at baseline. This analysis excluded participants who were defined as underweight at baseline.

Measurements: Information was collected on age, gender, occlusal force, the number of teeth, BMI, socioeconomic factors, medical history, the number of daily prescription medications, cognitive function, depressive symptoms, hand grip strength, and physical function. Maximal occlusal force was measured with a pressure-sensitive sheet. Nutritional status was assessed using BMI, and participants with BMI <21.5 were defined as underweight. Then, they were divided into two groups: a "BMI declined" group who were defined as underweight at either 3- or 6-year follow-up survey, and a "BMI maintained" group who were not defined as underweight at both follow-up surveys. Logistic generalized estimating equation (GEE) models were used to assess the effect of occlusal force and the number of teeth at baseline on decline in BMI over 3 or 6 years, after adjusting for possible covariates associated with nutritional status.

Results: The final analysis included 704 participants. Eighty-six (12.2%) participants were classified into the BMI declined group. Logistic GEE models showed that the number of teeth was not significantly associated with decline in BMI. However, occlusal force was significantly associated with decline in BMI (odds ratio = 0.90, 95% confidence interval = 0.83-0.97) after adjusting for covariates.

Conclusion: Participants with lower occlusal force were more likely to be in the BMI less than 21.5 kg/m . The findings suggest that to prevent decline in oral function is important to maintain nutritional status.
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http://dx.doi.org/10.1111/jgs.17106DOI Listing
July 2021

Association between physical function and onset of coronary heart disease in a cohort of community-dwelling older populations: The SONIC study.

Arch Gerontol Geriatr 2021 Jul-Aug;95:104386. Epub 2021 Mar 4.

Department of Health Promotion System Sciences, Division of Health Sciences, Graduate School of Medicine, Osaka University; Department of Geriatric and General Medicine, Graduate School of Medicine, Osaka University. Electronic address:

Background: Physical function is a strong predictor of the adverse outcomes of cardiovascular disease in older populations. However, studies of healthy older people on the prevention of coronary heart disease (CHD) are very limited.

Objectives: We prospectively examined the association of walking speed and handgrip strength with CHD in the community-dwelling older populations.

Methods: The study cohort in Japan included 1272 older people free from heart disease at the baseline. Physical function was identified based on walking speed and handgrip strength assessment at the survey site. Any new case of CHD was identified based on a self-reported doctor's diagnosis. Cox-proportion hazard models were adjusted for covariate factors to examine the CHD risk.

Results: During the 7-year follow-up, 45 new cases of CHD (25 men and 20 women) were documented. Slow walking speed was strongly associated with CHD risk after adjusting for all confounding factors in the total participants and women (hazard ratio (HR)= 2.53, 95%confidence interval (CI), 1.20-5.33, p=0.015, and HR= 4.78, 95% CI,1.07-21.35, p=0.040, respectively), but not in men. Weak grip strength was associated with CHD after age-adjustment (HR= 2.45, 95%CI, 1.03-5.81, p=0.043) only in men. However, after additional multivariate adjustment, the associations were getting weaker.
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http://dx.doi.org/10.1016/j.archger.2021.104386DOI Listing
June 2021

RAGE ligands stimulate angiotensin II type I receptor (AT1) via RAGE/AT1 complex on the cell membrane.

Sci Rep 2021 Mar 11;11(1):5759. Epub 2021 Mar 11.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Japan.

The receptor for advanced glycation end-products (RAGE) and the G protein-coupled angiotensin II (AngII) type I receptor (AT1) play a central role in cardiovascular diseases. It was recently reported that RAGE modifies AngII-mediated AT1 activation via the membrane oligomeric complex of the two receptors. In this study, we investigated the presence of the different directional crosstalk in this phenomenon, that is, the RAGE/AT1 complex plays a role in the signal transduction pathway of RAGE ligands. We generated Chinese hamster ovary (CHO) cells stably expressing RAGE and AT1, mutated AT1, or AT2 receptor. The activation of two types of G protein α-subunit, Gq and Gi, was estimated through the accumulation of inositol monophosphate and the inhibition of forskolin-induced cAMP production, respectively. Rat kidney epithelial cells were used to assess RAGE ligand-induced cellular responses. We determined that RAGE ligands activated Gi, but not Gq, only in cells expressing RAGE and wildtype AT1. The activation was inhibited by an AT1 blocker (ARB) as well as a RAGE inhibitor. ARBs inhibited RAGE ligand-induced ERK phosphorylation, NF-κB activation, and epithelial-mesenchymal transition of rat renal epithelial cells. Our findings suggest that the activation of AT1 plays a central role in RAGE-mediated cellular responses and elucidate the role of a novel molecular mechanism in the development of cardiovascular diseases.
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http://dx.doi.org/10.1038/s41598-021-85312-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952713PMC
March 2021

The endocytosis of oxidized LDL via the activation of the angiotensin II type 1 receptor.

iScience 2021 Feb 21;24(2):102076. Epub 2021 Jan 21.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Arrestin-dependent activation of a G-protein-coupled receptor (GPCR) triggers endocytotic internalization of the receptor complex. We analyzed the interaction between the pattern recognition receptor (PRR) lectin-like oxidized low-density lipoprotein (oxLDL) receptor (LOX-1) and the GPCR angiotensin II type 1 receptor (AT1) to report a hitherto unidentified mechanism whereby internalization of the GPCR mediates cellular endocytosis of the PRR ligand. Using genetically modified Chinese hamster ovary cells, we found that oxLDL activates Gαi but not the Gαq pathway of AT1 in the presence of LOX-1. Endocytosis of the oxLDL-LOX-1 complex through the AT1-β-arrestin pathway was demonstrated by real-time imaging of the membrane dynamics of LOX-1 and visualization of endocytosis of oxLDL. Finally, this endocytotic pathway involving GPCR kinases (GRKs), β-arrestin, and clathrin is relevant in accumulating oxLDL in human vascular endothelial cells. Together, our findings indicate that oxLDL activates selective G proteins and β-arrestin-dependent internalization of AT1, whereby the oxLDL-LOX-1 complex undergoes endocytosis.
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http://dx.doi.org/10.1016/j.isci.2021.102076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890409PMC
February 2021

A pressor dose of angiotensin II has no influence on the angiotensin-converting enzyme 2 and other molecules associated with SARS-CoV-2 infection in mice.

FASEB J 2021 03;35(3):e21419

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.
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http://dx.doi.org/10.1096/fj.202100016RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995007PMC
March 2021

Carotenemia induced by iron deficiency.

BMJ Case Rep 2021 Jan 28;14(1). Epub 2021 Jan 28.

Geriatric Medicine, Osaka University Hospital, Suita, Osaka, Japan.

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http://dx.doi.org/10.1136/bcr-2020-236597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845686PMC
January 2021

Further promotion of "the JSH plan for the future" conscious of new normal after/with COVID-19: message from the new president of the Japanese Society of Hypertension.

Authors:
Hiromi Rakugi

Hypertens Res 2021 01;44(1):4-6

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan.

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http://dx.doi.org/10.1038/s41440-020-00581-2DOI Listing
January 2021

Sex Differences in Renal Outcomes After Medical Treatment for Bilateral Primary Aldosteronism.

Hypertension 2021 02 28;77(2):537-545. Epub 2020 Dec 28.

Department of Endocrinology and Metabolism, National Hospital Organization Kyoto Medical Center, Japan (M.T., M.N.).

A higher incidence of bilateral primary aldosteronism in women is reported. Treatment of bilateral primary aldosteronism usually involves mineralocorticoid receptor antagonists. However, the impact of sex on renal outcomes is unknown. We compared renal outcomes between the sexes after mineralocorticoid receptor antagonist initiation by analyzing data obtained from 415 female and 313 male patients with bilateral primary aldosteronism who were treated with spironolactone or eplerenone in the JPAS (Japan Primary Aldosteronism Study). Over the course of 5 years, the temporal reduction in the estimated glomerular filtration rate was greater in women than in men (<0.001). Systolic blood pressure levels were equal between the sexes, despite higher doses of antihypertensive drugs in men. The mean of the annual decline in estimated glomerular filtration rate during what we termed the late phase, or 6 to 60 months after mineralocorticoid receptor antagonist initiation, was larger in women than in men after adjusting for patient characteristics (-1.33 mL/min per 1.73 m per year versus -1.04 mL/min per 1.73 m per year, <0.01). Female sex was a significant predictor of greater annual decline during the late phase in patients taking spironolactone but not in those taking eplerenone. Spironolactone use and diabetes were independent predictors of a greater annual decline in estimated glomerular filtration rate during the late phase in women. These findings suggest that female sex is associated with poorer renal outcomes in patients receiving mineralocorticoid receptor antagonist for bilateral primary aldosteronism.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.16449DOI Listing
February 2021

Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dysfunction.

Hypertens Res 2021 05 16;44(5):489-497. Epub 2020 Dec 16.

Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Renin-angiotensin system inhibitors are recommended for treating hypertension with chronic kidney disease. The addition of a mineralocorticoid receptor blocker may be one option to achieve target blood pressure. We investigated the efficacy and safety of esaxerenone, a mineralocorticoid receptor blocker, in Japanese hypertensive patients with moderate kidney dysfunction. Two multicenter, open-label, nonrandomized dose escalation studies were conducted to investigate esaxerenone monotherapy and add-on therapy to renin-angiotensin system inhibitor treatment. Esaxerenone therapy was initiated at 1.25 mg/day and titrated to 2.5 and then 5 mg/day for a treatment duration of 12 weeks. Primary endpoints were changes from baseline in sitting systolic and diastolic blood pressure. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also assessed. Thirty-three patients received monotherapy, and 58 received add-on therapy; the mean baseline estimated glomerular filtration rates were 51.9 and 50.9 mL/min/1.73 m, respectively. The esaxerenone dosage was increased to ≥2.5 mg/day in 100% (n = 33) and 93.1% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. Reductions in sitting blood pressure from baseline to the end of treatment were similar (monotherapy: -18.5/-8.8 mmHg; add-on therapy: -17.8/-8.1 mmHg; both P < 0.001). The antihypertensive effects of esaxerenone were consistent across patient subgroups. A serum K level ≥5.5 mEq/L was observed in seven patients (12.1%) receiving add-on therapy but in none receiving monotherapy. All increases in serum K levels were transient, and no patient met predefined serum K level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment owing to kidney function decline. Esaxerenone was effective and well tolerated in hypertensive patients with moderate kidney dysfunction.
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http://dx.doi.org/10.1038/s41440-020-00585-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099724PMC
May 2021

Insight into the Role of Angiopoietins in Ageing-Associated Diseases.

Cells 2020 12 8;9(12). Epub 2020 Dec 8.

Department of Clinical Gene Therapy, Center of Medical Innovation and Translational Research, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Angiopoietin (Ang) and its receptor, TIE signaling, contribute to the development and maturation of embryonic vasculature as well as vascular remodeling and permeability in adult tissues. Targeting both this signaling pathway and the major pathway with vascular endothelial growth factor (VEGF) is expected to permit clinical applications, especially in antiangiogenic therapies against tumors. Several drugs targeting the Ang-TIE signaling pathway in cancer patients are under clinical development. Similar to how cancer increases with age, unsuitable angiogenesis or endothelial dysfunction is often seen in other ageing-associated diseases (AADs) such as atherosclerosis, Alzheimer's disease, type 2 diabetes, chronic kidney disease and cardiovascular diseases. Thus, the Ang-TIE pathway is a possible molecular target for AAD therapy. In this review, we focus on the potential role of the Ang-TIE signaling pathway in AADs, especially non-cancer-related AADs. We also suggest translational insights and future clinical applications of this pathway in those AADs.
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http://dx.doi.org/10.3390/cells9122636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762563PMC
December 2020

Glycemic Control and Insulin Improve Muscle Mass and Gait Speed in Type 2 Diabetes: The MUSCLES-DM Study.

J Am Med Dir Assoc 2021 04 2;22(4):834-838.e1. Epub 2020 Dec 2.

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Japan. Electronic address:

Objectives: Type 2 diabetes is a risk factor for sarcopenia. Evidence on the prevention of sarcopenia using blood glucose-lowering therapy is limited. We aimed to examine the relationship between changes in glycemic control and sarcopenia and the effect of antidiabetic agents against sarcopenia in patients with type 2 diabetes.

Design: We conducted an observational longitudinal study.

Setting And Participants: In total, 588 Japanese patients with diabetes of an ongoing multicenter study completed 1-year follow-up measurements for sarcopenia and clinical data.

Methods: The data set of the Multicenter Study for Clarifying Evidence for Sarcopenia in patients with Diabetes Mellitus (the MUSCLES-DM study) was analyzed.

Results: During the follow-up period, the frequency of sarcopenia marginally increased, and the means of skeletal muscle mass index (SMI), handgrip strength, and gait speed did not show any changes. However, on dividing into 5 groups depending on the degree of changes in glycated hemoglobin (HbA) value, the patients with a decrease of ≥1% in HbA exhibited a significant increase in SMI. Our analysis revealed similar results for gait speed but not handgrip strength. Using the multiple linear regression model, we identified that a ≥1% decrease in HbA value was an independent determinant of the changes in SMI and gait speed. We also determined that insulin use at baseline was an independent factor for the changes in SMI.

Conclusions And Implications: Correction of poor glycemic control and use of insulin were significantly associated with the increase in skeletal muscle mass or gait speed in Japanese patients with type 2 diabetes. The current finding increases our understanding of the importance of glycemic control for the prevention of cardiovascular diseases and sarcopenia.
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http://dx.doi.org/10.1016/j.jamda.2020.11.003DOI Listing
April 2021

ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19.

Clin Sci (Lond) 2020 11;134(22):3047-3062

Department of Geriatric and General Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin-angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.
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http://dx.doi.org/10.1042/CS20200486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687025PMC
November 2020

Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone.

Hypertens Res 2021 04 20;44(4):371-385. Epub 2020 Nov 20.

Medical Science Department, Daiichi Sankyo Co., Ltd., 3-5-1, Nihonbashi Honcho, Chuo-ku, Tokyo, 103-8426, Japan.

The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I-III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.
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http://dx.doi.org/10.1038/s41440-020-00569-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019656PMC
April 2021

Efficacy and safety of esaxerenone (CS-3150), a newly available nonsteroidal mineralocorticoid receptor blocker, in hypertensive patients with primary aldosteronism.

Hypertens Res 2021 04 16;44(4):464-472. Epub 2020 Nov 16.

Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo, 140-8710, Japan.

Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.
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http://dx.doi.org/10.1038/s41440-020-00570-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019657PMC
April 2021

Association between uric acid and atherosclerosis in community-dwelling older people: The SONIC study.

Geriatr Gerontol Int 2021 Jan 9;21(1):94-101. Epub 2020 Nov 9.

Department of Health Science, Osaka University Graduate School of Medicine, Osaka, Japan.

Aim: The association between serum uric acid (UA) and atherosclerosis in old people is controversial. Therefore, in this study, we clarified this association by assessing serum UA and common carotid atherosclerosis examined by carotid ultrasound in community-dwelling older people in their 70s, 80s and 90s in the SONIC study.

Methods: A cross-sectional study was conducted involving 538 men and 577 women recruited from the community. The analysis was performed using serum UA as the explanatory variable and the maximum carotid intima-media thickness (max-CIMT) and mean-IMT as the dependent variables. The analysis was performed by multiple regression using traditional risk factors for atherosclerosis as adjustment variables.

Results: Analysis of the association between serum UA and IMT revealed a significant correlation only in women >70 years old. Max-CIMT (β = 0.081, 95% CI = 0.026, 0.136; P = 0.004) and mean-IMT (β = 0.015, 95% CI = 0.003, 0.029; P = 0.016) were significant. In the analysis of each age group, a significant correlation was only found in women in their 70s for mean-IMT (β = 0.031, 95% CI = 0.008, 0.053; P = 0.008).

Conclusion: In community-dwelling women aged about 70 years old, elevated serum UA may be an independent risk factor for IMT thickening as a surrogate marker for atherosclerosis. Geriatr Gerontol Int 2021; 21: 94-101.
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http://dx.doi.org/10.1111/ggi.14081DOI Listing
January 2021

Effect of the Nonsteroidal Mineralocorticoid Receptor Blocker, Esaxerenone, on Nocturnal Hypertension: A Post Hoc Analysis of the ESAX-HTN Study.

Am J Hypertens 2021 05;34(5):540-551

Daiichi Sankyo Co., Ltd., Tokyo, Japan.

Background: Nocturnal hypertension is an important phenotype of abnormal diurnal blood pressure (BP) variability and a known risk marker for target organ damage and cardiovascular events. This study aimed to assess the differential BP-lowering effects of esaxerenone vs. eplerenone on nocturnal BP in hypertensive patients with different nocturnal dipping patterns.

Methods: This was a post hoc analysis of the "Esaxerenone (CS-3150) Compared to Eplerenone in Patients with Essential Hypertension" study (NCT02890173), which was a phase 3, multicenter, randomized, controlled, double-blind, parallel-group clinical study conducted in Japan. Ambulatory BP monitoring data were collected.

Results: Patients (n = 1,001) were randomized to esaxerenone 2.5 mg/day (n = 331) or 5 mg/day (n = 338), or eplerenone 50 mg/day (n = 332). Reductions in nighttime systolic BP (95% confidence interval) were significantly greater with 2.5 and 5 mg/day esaxerenone vs. eplerenone (-2.6 [-5.0, -0.2] and -6.4 mm Hg [-8.8, -4.0], respectively). Esaxerenone significantly reduced nighttime BP from baseline compared with eplerenone in non-dippers with previously uncontrolled BP. In addition, esaxerenone did not markedly alter nighttime BP in extreme dipper patients. In the esaxerenone 5 mg/day group, esaxerenone-induced decreases in nighttime BP were greater than eplerenone-induced decreases in older patients.

Conclusions: Esaxerenone may be an effective treatment option for nocturnal hypertension, especially in older patients and those with a non-dipper pattern of nocturnal BP.
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http://dx.doi.org/10.1093/ajh/hpaa155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140658PMC
May 2021

Association of periodontal disease with atherosclerosis in 70-year-old Japanese older adults.

Odontology 2021 Apr 4;109(2):506-513. Epub 2020 Nov 4.

Department of Periodontology, Osaka University Graduate School of Dentistry, Suita, Osaka, Japan.

Periodontal disease and arteriosclerotic disease are greatly affected by aging. In this study, the association of conventional risk factors and periodontal disease with atherosclerosis was longitudinally examined in Japanese older adults. Subjects in this study were 490 community-dwelling septuagenarians (69-71 years) randomly recruited from the Basic Resident Registry of urban or rural areas in Japan. At the baseline examination, all subjects underwent socioeconomic and medical interviews; medical examinations, including examinations for carotid atherosclerosis, hypertension, diabetes mellitus, and dyslipidemia; and conventional dental examinations, including a tooth count and measurement of probing pocket depth (PPD). After 3 years, 182 septuagenarians who had no atherosclerosis at the baseline examination were registered and received the same examination as at the baseline. In the re-examination conducted 3 years after the baseline survey, 131 (72.0%) of the 182 participants who had no atherosclerosis at the baseline examination were diagnosed with carotid atherosclerosis. Adjusting and analyzing the mutual relationships of the conventional risk factors for atherosclerosis by multiple logistic regression analysis for the 171 septuagenarians with a full set of data, the proportion of teeth with PPD ≥ 4 mm was independently related to the prevalence of atherosclerosis (odds ratio: 1.029, P < 0.022). This longitudinal study of Japanese older adults suggests that periodontal disease is associated with the onset/progression of atherosclerosis. Maintaining a healthy periodontal condition may be an important factor in preventing the development and progression of atherosclerosis.
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http://dx.doi.org/10.1007/s10266-020-00567-zDOI Listing
April 2021

The Japan Geriatrics Society consensus statement "recommendations for older persons to receive the best medical and long-term care during the COVID-19 outbreak-considering the timing of advance care planning implementation".

Geriatr Gerontol Int 2020 Dec 2;20(12):1112-1119. Epub 2020 Nov 2.

Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Since the end of 2019, a life-threatening infectious disease (coronavirus disease 2019: COVID-19) has spread globally, and numerous victims have been reported. In particular, older persons tend to suffer more severely when infected with a novel coronavirus (SARS-CoV-2) and have higher case mortality rates; additionally, outbreaks frequently occur in hospitals and long-term care facilities where most of the residents are older persons. Unfortunately, it has been stated that the COVID-19 pandemic has caused a medical collapse in some countries, resulting in the depletion of medical resources, such as ventilators, and triage based on chronological age. Furthermore, as some COVID-19 cases show a rapid deterioration of clinical symptoms and accordingly, the medical and long-term care staff cannot always confirm the patient's values and wishes in time, we are very concerned as to whether older patients are receiving the medical and long-term care services that they wish for. It was once again recognized that it is vital to implement advance care planning as early as possible before suffering from COVID-19. To this end, in August 2020, the Japan Geriatrics Society announced ethical recommendations for medical and long-term care for older persons and emphasized the importance of conducting advance care planning at earlier stages. Geriatr Gerontol Int 2020; 20: 1112-1119.
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http://dx.doi.org/10.1111/ggi.14075DOI Listing
December 2020
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