Language：English   Publishing type：Research paper (scientific journal)  

Chronic kidney disease-mineral and bone disorder (CKD-MBD) are recognized as a systemic disease affecting the prognosis of patients with CKD. Proper management of CKD-MBD is important to improve the prognosis of patients with CKD. Although proteinuria is recognized as a poor prognostic factor in these patients, few reports have examined its association with CKD-MBD. We examined the association between proteinuria and CKD-MBD using data from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex). Among the patients registered in the J-CKD-DB-Ex, 30,977 with CKD stages G2-G5 who had serum creatinine, albumin, calcium, and phosphate concentrations measured at least once and urinalysis performed were included. The patients were divided into four groups (negative, 1+, 2+, and 3+) according to the degree of proteinuria. The association between proteinuria and CKD-MBD was examined by a logistic regression analysis. In a model adjusted for age, sex, diabetes, and the estimated glomerular filtration rate (eGFR), the odds ratio of the 3 + group compared with the negative group significantly increased to 2.67 (95% confidence interval, 2.29-3.13) for hyperphosphatemia, 2.68 (1.94-3.71) for hypocalcemia, and 1.56 (1.24-1.98) for hypomagnesemia. Proteinuria is associated with hyperphosphatemia, hypocalcemia, and hypomagnesemia in patients with CKD independently of eGFR.

DOI： 10.1038/s41598-024-79291-5

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The new Japanese guidelines for primary aldosteronism introduce a category in the judgment of functional confirmatory tests that is called the "borderline range," which is rare in the other international guidelines. The clinical characteristics of this borderline group are not yet understood. To investigate whether this borderline group has any significant differences in terms of target organ damage, we used data from a Japanese nationwide registry (JPAS-II) of individuals with primary aldosteronism or essential hypertension to compare the borderline group with the definitive-positive group and the negative group. We analyzed the cases of 1785 patients based on their captopril-challenge test results. Since the JPAS-II database contains plasma aldosterone concentration values obtained based on both radioimmunoassay (n = 1555) and chemiluminescent enzyme immunoassay (n = 230) principles, we converted these values to their equivalents as if measured by chemiluminescent enzyme immunoassay and conducted all analyses under the simulated condition. Multicovariate-adjusted models revealed significant prevalance odds ratios for chronic kidney disease (2.01, 95% confidence interval: 1.13 to 3.61), electrocardiographic abnormalities (1.66, 95% confidence interval: 1.16 to 2.37). No significant difference was observed between the borderline and negative groups in these assessments (odds ratio [95% confidence interval] for chronic kidney disease: 0.73 [0.26 to 2.02] and electrocardiographic abnormalities: 1.01 [0.60 to 1.70]). We confirmed that the prevalence of target organ damage increases linearly as the aldosterone-to-renin ratio rises following the captopril challenge test. These results provide material to consider regarding the significance of the provisionally established borderline group.

DOI： 10.1038/s41440-024-01943-w

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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A regulatory mechanism for SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule, is incompletely understood. Here, we report an important regulation of SLC family transporter by SETD2, a chromatin remodeling gene whose alterations have been found in a subset of kidney cancers. Kidney-specific inactivation of Setd2 resulted in hypovolemia with excessive urine excretion in mouse and interestingly, RNA-sequencing analysis of Setd2-deficient murine kidney exhibited decreased expressions of SLC family transporters, critical transporters for sodium and glucose reabsorptions in renal tubule. Importantly, inactivation of Setd2 in murine kidney displayed attenuated dapagliflozin-induced diuresis and glucose excretion, further supporting that SETD2 might regulate SLCfamily transporter-mediated sodium and glucose reabsorptions in renal tubule. These data uncover an important regulation of SLC family transporter by SETD2, which may illuminate a crosstalk between metabolism and epigenome in renal tubule.

DOI： 10.1016/j.bbrc.2024.150730

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Objective Patients undergoing maintenance dialysis are at a higher risk of morbidity and mortality due to severe coronavirus disease 2019 (COVID-19) than the general population. However, longitudinal data regarding this subpopulation of patients are lacking. We therefore examined the prognosis of patients with COVID-19 undergoing maintenance dialysis between 2020 and 2023. In addition, we explored the factors correlated with COVID-19 severity, focusing on the transition thereof throughout the observational period. Methods The primary outcome was the progression to severe or fatal COVID-19. We evaluated the correlation between the primary outcome and baseline demographic and clinical characteristics of patients. Patients undergoing maintenance dialysis who were hospitalized for mild-to-moderate COVID-19 between February 2020 and April 2023 were enrolled at four institutions in Kanagawa, Japan. Results Of the 173 patients, 7 (4.0%) developed severe COVID-19, and 12 (6.9%) died. The severe/death cohort was significantly older, with a higher percentage of unvaccinated patients than the non-severe cohort (58.2% and 25.0%, respectively; p=0.016). Thymus and activation-regulated chemokine levels on admission were lower in the severe/death cohort than in the non-severe cohort, albeit not to a statistically significant degree (148±84 mg/dL and 342±657 pg/mL, respectively; p=0.082). A multivariate logistic regression analysis revealed that the odds ratio for severe morbidity or death was 0.23 (95% confidence interval: 0.07-0.75) for vaccinated patients. Conclusion In patients undergoing maintenance dialysis, the severity rate of COVID-19 is approximately 10%. Vaccination was correlated with a reduced risk of severe COVID-19.

DOI： 10.2169/internalmedicine.4199-24

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BACKGROUND: The benefit of prehospital 12‑lead electrocardiogram (PH-ECG) performed by emergency medical service personnel at the site of first medical contact (FMC) in patients with ST-segment elevation myocardial infarction (STEMI) with cardiogenic shock (CS-STEMI) remains unclear. This study aimed to investigate the effect of PH-ECG on door-to-device time in patients with CS-STEMI. METHODS: This study enrolled CS-STEMI (Killip class IV) patients who were transferred directly to hospitals by ambulance (n = 517) from the Kanagawa Acute Cardiovascular Registry database. Patients were divided into PH-ECG (+) (n = 270) and PH-ECG (-) (n = 247) groups. Patients who experienced out-of-hospital cardiac arrest, who did not undergo emergent coronary intervention, or whose data were missing were excluded. Patient characteristics, FMC-to-door time, door-to-device time, and in-hospital mortality were compared between the groups. RESULTS: The patient backgrounds of the PH-ECG (+) and PH-ECG (-) groups were comparable. The peak creatinine kinase level was greater in the PH-ECG (+) group than in the PH-ECG (-) group [2756 (1292-6009) IU/ml vs. 2270 (957-5258) IU/ml, p = 0.048]. The FMC-to-door time was similar between the two groups [25 (20-33) min vs. 27 (20-35) min, p = 0.530], while the door-to-device time was significantly shorter in the PH-ECG group [74 (52-103) min vs. 83 (62-111) min, p = 0.007]. In-hospital mortality did not differ between the two groups (18 % vs. 21 %, p = 0.405). Multivariable logistic regression analyses revealed that PH-ECG (+) was independently associated with a door-to-device time < 60 min [odds ratio (95 % confidence intervals): 1.88 (1.24-2.83), p = 0.003]. CONCLUSIONS: PH-ECG was significantly associated with shorter door-to-device times in patients with CS-STEMI. Further studies with larger populations and more defined protocols are required to evaluate the utility of PH-ECG in patients with CS-STEMI.

DOI： 10.1016/j.jjcc.2024.08.004

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Hypertension is an uncommon manifestation of Behcet's disease, which is also an uncommon cause of renovascular hypertension. We herein report a case of malignant hypertension associated with unilateral renal artery stenosis due to vascular Behcet's disease. A 19-year-old man, who had no significant medical history, was referred to ophthalmology at our hospital because he was suspected to have uveitis and Vogt-Koyanagi-Harada syndrome. In addition to poor eyesight, he had been aware of a fever, loss of appetite, and weight loss for a month. He was admitted with markedly elevated blood pressure (222/140 mmHg), hypertensive retinopathy, and acute kidney injury, who was diagnosed with malignant hypertension. Laboratory findings showed high plasma renin activity and plasma aldosterone concentration, hypokalemia, and elevated inflammatory response. Computed tomography showed an atrophic right kidney and a compensatorily enlarged left kidney. Renal computed tomography angiography revealed severe and diffuse stenosis of the right renal artery, and stenosis of the ostium of celiac artery. Since he was suspected to have uveitis and his inflammatory responses were elevated on admission, we listed Behcet's disease as a differential diagnosis. Medical interview and examination focusing on Behcet's disease revealed that the patient had recurrent oral aphthous lesions and folliculitis, and a positive pathergy test, which led to the patient being diagnosed with vascular Behcet's disease. After admission, his blood pressure was well controlled with multiple antihypertensive drugs including an angiotensin receptor/neprilysin inhibitor, and his oral aphthous lesions and skin lesion were improved with colchicine. When young men who are at a higher risk for vascular Behcet's disease show renovascular hypertension with an elevated inflammatory reaction, vascular Behcet's disease should be considered as a differential diagnosis.

DOI： 10.1007/s13730-024-00918-7

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BACKGROUND: Weight loss is a poor prognostic factor in patients with chronic heart failure (HF). However, whether the same is true for hospitalized patients with HF is unknown, even though hospitalization is the first opportunity for many patients to be diagnosed with HF. This study aimed to investigate the prognostic value of weight loss in patients hospitalized for HF. METHODS: This was a post-hoc analysis of the FRAGILE-HF study, a prospective multi-center, observational study including 1,332 hospitalized older (≥65 years) patients with HF. The primary outcome was all-cause death within two years of discharge. RESULTS: Self-reported body weight data one year prior to hospital admission were available for 1,106 patients (83.0%) and were compared with their weight after decongestion therapy. The median weight change was -6.9% [-2.4 - -11.9] and 86.8% of the overall cohort experienced some weight loss. Whereas patients with weight loss ≥ 5%, which is a well-validated cut-off in chronic HF, had comparable mortality to those with less weight loss (p = 0.96 by log-rank test), patients with weight loss > 12%, the lowest quartile value, had higher mortality than those with less weight loss (p = 0.024 for all-cause mortality, p = 0.028 for non-cardiovascular mortality, and p = 0.28 for cardiovascular mortality, respectively). In a Cox proportional hazard model, > 12% weight loss was associated with high mortality after adjusting for known prognostic factors and history of malignancy (adjusted hazard ratio: 1.485 [1.070-2.062], p=0.018). CONCLUSION: Weight loss derived from patient-reported body weight one year before hospitalization was significantly associated with increased mortality after discharge, mainly due to non-cardiovascular etiology, in elderly patients hospitalized for HF.

DOI： 10.1093/ehjqcco/qcae058

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s13730-024-00913-y

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Other Link： https://link.springer.com/article/10.1007/s13730-024-00913-y/fulltext.html

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BACKGROUND: Renoprotective effects of sodium glucose transporter 2 (SGLT2) inhibitors, including dapagliflozin, were observed in randomized controlled trials (RCTs). The suspected underlying mechanism is a correction of hyperfiltration, observed as an "initial dip". Whether SGLT2 inhibitors can attenuate the rate of decline in the estimated glomerular filtration rate (eGFR) in clinical settings, even when considering the pre-treatment decline rate, is unknown. Although several RCTs identified an association between the initial dip and long-term renal prognoses, a conclusion has not been reached. METHODS: We collected the eGFR data of patients for whom dapagliflozin was initiated in our hospital and then calculated their eGFR slopes before and after the start of the treatment. We investigated the changes in the eGFR slopes (ΔeGFR slope) and the association between the ΔeGFR slope and the initial dip. Risks for rapid eGFR decliners (eGFR slope < - 3 mL/min/1.73 m2/year) were also examined. RESULTS: The eGFR slope was significantly milder after dapagliflozin treatment (p < 0.01). A deeper initial dip was associated with a milder rate of eGFR decline (adjusted beta: - 0.29, p < 0.001). Dapagliflozin treatment reduced the proportion of rapid eGFR decliners from 52.9 to 14.7%, and a smaller initial dip was identified as a significant risk for post-treatment rapid eGFR decline (adjusted odds ratio: 1.73, p < 0.05). CONCLUSIONS: Compared to before the administration of dapagliflozin, the rate of eGFR decline was significantly milder after its administration. The initial dip was significantly associated with long-term renoprotective effects and may be a useful predictor of treatment response.

DOI： 10.1007/s10157-024-02532-4

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AIM: Sodium-glucose cotransporter 2 (SGLT2) inhibitors often cause a transient decrease in glomerular filtration rate (GFR) shortly after the initiation, referred to as the 'initial drop'. However, the clinical significance of this initial drop in real-world practice remains unclear. MATERIALS AND METHODS: Using the nationwide Japan Chronic Kidney Disease Database, we examined factors that affected the initial drop, in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). We also evaluated the effects of the initial drop on a composite kidney outcome (a decline in GFR of ≥50% or progression to end-stage kidney disease). RESULTS: Data from 2053 patients with CKD and T2DM newly prescribed an SGLT2 inhibitor were analysed. The follow-up period after SGLT2 inhibitor administration was 1015 days (interquartile range: 532, 1678). Multivariate linear regression models revealed that the concomitant use of the renin-angiotensin system inhibitors and diuretics, urinary protein levels ≥2+, and changes in GFR before the initiation of the SGLT2 inhibitor were associated with a larger initial GFR decline (β = -0.609, p = .039; β = -2.298, p < .001; β = -0.936, p = .048; β = -0.079, p < .001, respectively). Patients in the quartile with the largest initial GFR decline experienced a higher incidence of the subsequent composite kidney outcome than those in the other quartiles (p < .001). CONCLUSIONS: The concomitant use of renin-angiotensin system inhibitors and diuretics, higher urine protein levels and pre-treatment GFR changes were associated with a larger initial GFR decline. Of these factors, the use of a diuretic had the largest effect. Furthermore, patients with CKD and T2DM experiencing an excessive initial GFR drop might be at a higher risk of adverse kidney outcomes.

DOI： 10.1111/dom.15611

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Language：English  

DOI： 10.1038/s41746-024-01158-w

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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INTRODUCTION: Peritoneal dialysis (PD) is a mode of therapy in which the patients themselves actively participate in the care of their own disease. We examined a possible association of salt reduction before starting dialysis with PD technique survival. METHODS: This retrospective cohort study included 42 patients who started PD between April 2014 and March 2018. Participants were allocated to two groups based on their estimated daily salt intake before the initiation of dialysis: patients with an estimated daily salt intake <6 g/day were allocated to the appropriate salt intake group (AS group), while the rest were assigned to the high salt intake group (HS group). RESULTS: During a median follow-up of 47 months, PD technique survival, defined by death or transition to hemodialysis, was significantly lower in the HS group compared to the AS group. CONCLUSION: Successful salt reduction before dialysis introduction is associated with better PD technique survival.

DOI： 10.1111/1744-9987.14167

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Aim

To conduct a post hoc subgroup analysis of patients with type 2 diabetes (T2D) from the RECAP study, who were treated with sodium‐glucose cotransporter‐2 (SGLT2) inhibitor and glucagon‐like peptide 1 receptor agonist (GLP‐1RA) combination therapy, focusing only on those patients who had chronic kidney disease (CKD), to examine whether the composite renal outcome differed between those who received SGLT2 inhibitor treatment first and those who received a GLP‐1RA first.

Methods

We included 438 patients with CKD (GLP‐1RA‐first group, n = 223; SGLT2 inhibitor‐first group, n = 215) from the 643 T2D patients in the RECAP study. The incidence of the composite renal outcome, defined as progression to macroalbuminuria and/or a ≥50% decrease in estimated glomerular filtration rate (eGFR), was analysed using a propensity score (PS)‐matched model. Furthermore, we calculated the win ratio for these composite renal outcomes, which were weighted in the following order: (1) both a ≥50% decrease in eGFR and progression to macroalbuminuria; (2) a decrease in eGFR of ≥50% only; and (3) progression to macroalbuminuria only.

Results

Using the PS‐matched model, 132 patients from each group were paired. The incidence of renal composite outcomes did not differ between the two groups (GLP‐1RA‐first group, 10%; SGLT2 inhibitor‐first group, 17%; odds ratio 1.80; 95% confidence interval [CI] 0.85 to 4.26; p = 0.12). The win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was 1.83 (95% CI 1.71 to 1.95; p &lt; 0.001).

Conclusion

Although the renal composite outcome did not differ between the two groups, the win ratio of the GLP‐1RA‐first group versus the SGLT2 inhibitor‐first group was significant. These results suggest that, in GLP‐1RA and SGLT2 inhibitor combination therapy, the addition of an SGLT2 inhibitor to baseline GLP‐1RA treatment may lead to more favourable renal outcomes.

DOI： 10.1111/dom.15652

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DOI： 10.3390/jvd3020014

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper (scientific journal)  

We evaluated the effectiveness of a mobile health (mHealth) intervention for diabetic kidney disease patients by conducting a 12-month randomized controlled trial among 126 type 2 diabetes mellitus patients with moderately increased albuminuria (urinary albumin-to-creatinine ratio (UACR): 30-299 mg/g creatinine) recruited from eight clinical sites in Japan. Using a Theory of Planned Behavior (TPB) behavior change theory framework, the intervention provides patients detailed information in order to improve patient control over exercise and dietary behaviors. In addition to standard care, the intervention group received DialBetesPlus, a self-management support system allowing patients to monitor exercise, blood glucose, diet, blood pressure, and body weight via a smartphone application. The primary outcome, change in UACR after 12 months (used as a surrogate measure of renal function), was 28.8% better than the control group's change (P = 0.029). Secondary outcomes also improved in the intervention group, including a 0.32-point better change in HbA1c percentage (P = 0.041). These improvements persisted when models were adjusted to account for the impacts of coadministration of drugs targeting albuminuria (GLP-1 receptor agonists, SGLT-2 inhibitors, ACE inhibitors, and ARBs) (UACR: -32.3% [95% CI: -49.2%, -9.8%] between-group difference in change, P = 0.008). Exploratory multivariate regression analysis suggests that the improvements were primarily due to levels of exercise. This is the first trial to show that a lifestyle intervention via mHealth achieved a clinically-significant improvement in moderately increased albuminuria.

DOI： 10.1038/s41746-024-01114-8

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It has not yet been established whether angiotensin II receptor blockers (ARB), statins, and multiple drugs affect the severity of COVID-19. Therefore, we herein performed an observational study on the effects of 1st- and 2nd-generation ARB, statins, and multiple drugs, on COVID-19 in patients admitted to 15 Japanese medical facilities. The results obtained showed that ARB, statins, and multiple drugs were not associated with the primary outcome (odds ratio: 1.040, 95% confidence interval: 0.688-0.571; 0.696, 0.439-1.103; 1.056, 0.941-1.185, respectively), each component of the primary outcome (in-hospital death, ventilator support, extracorporeal membrane oxygenation support, and admission to the intensive care unit), or the secondary outcomes (oxygen administration, disturbed consciousness, and hypotension, defined as systolic blood pressure ≤90 mmHg). ARB were divided into 1st- and 2nd-generations based on their approval for use (before 2000 and after 2001), with the former consisting of losartan, candesartan, and valsartan, and the latter of telmisartan, olmesartan, irbesartan, and azilsartan. The difference of ARB generation was not associated with the primary outcome (odds ratio with 2nd-generation ARB relative to 1st-generation ARB: 1.257, 95% confidence interval: 0.613-2.574). The odd ratio for a hypotension as one of the secondary outcomes with 2nd-generation ARB was 1.754 (95% confidence interval: 1.745-1.763) relative to 1st-generation ARB. These results suggest that patients taking 2nd-generation ARB may be at a higher risk of hypotension than those taking 1st-generation ARB and also that careful observations are needed. Further studies are continuously needed to support decisions to adjust medications for co-morbidities.

DOI： 10.1038/s41440-024-01682-y

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DOI： 10.1007/s13730-024-00869-z

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AIM: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL. METHODS: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively. RESULTS: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment. CONCLUSION: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

DOI： 10.5551/jat.64639

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Single-nucleotide polymorphisms (SNP) of ATP2B1 gene are associated with essential hypertension but their association with resistant hypertension (RHT) remains unexplored. The authors examined the relationship between ATP2B1 SNPs and RHT by genotyping 12 SNPs in ATP2B1 gene of 1124 Japanese individuals with lifestyle-related diseases. Patients with RHT had inadequate blood pressure (BP) control using three antihypertensive drugs or used ≥4 antihypertensive drugs. Patients with controlled hypertension had BP controlled using ≤3 antihypertensive drugs. The association between each SNP and RHT was analyzed by logistic regression. The final cohort had 888 (79.0%) and 43 (3.8%) patients with controlled hypertension and RHT, respectively. Compared with patients homozygous for the minor allele of each SNP in ATP2B1, a significantly higher number of patients carrying the major allele at 10 SNPs exhibited RHT (most significant at rs1401982: 5.8% vs. 0.8%, p = .014; least significant at rs11105378: 5.7% vs. 0.9%, p = .035; most nonsignificant at rs12817819: 5.1% vs. 10%, p = .413). After multivariate adjustment for age, sex, systolic BP, and other confounders, the association remained significant for rs2681472 and rs1401982 (OR: 7.60, p < .05 and OR: 7.62, p = .049, respectively). Additionally, rs2681472 and rs1401982 were in linkage disequilibrium with rs11105378. This study identified two ATP2B1 SNPs associated with RHT in the Japanese population. rs1401982 was most closely associated with RHT, and major allele carriers of rs1401982 required significantly more antihypertensive medications. Analysis of ATP2B1 SNPs in patients with hypertension can help in early prediction of RHT and identification of high-risk patients who are more likely to require more antihypertensive medications.

DOI： 10.1111/jch.14785

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞Point ◎治療抵抗性高血圧は,「利尿薬を含む3剤の降圧薬を用いても血圧が目標まで下がらない状態」と定義される.◎コントロール不良高血圧や治療抵抗性高血圧では要因を鑑別することが重要である.◎利尿薬は高血圧薬物治療の重要な選択肢の1つであり,減塩が困難な場合や体液過剰の患者では特に有効である.◎治療抵抗性高血圧の薬物療法として,ミネラルコルチコイド受容体(MR)拮抗薬やアンジオテンシン受容体ネプリライシン阻害薬(ARNI)が有用である.

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Language：Japanese   Publisher：(株)医学書院  

＜文献概要＞はじめに 血圧は,心拍出量と末梢血管抵抗によって規定され,心拍出量は体液量と心収縮力によって決定する.これらの因子は食塩摂取量や交感神経系,レニン-アンジオテンシン-アルドステロン(renin-angiotensin-aldosterone:RAA)系などにより,さまざまな修飾を受ける.腎臓は血圧異常により障害を受ける一方で,血圧の規定因子の1つでもある.このように腎臓と血圧は密接な関係をもっている.本稿では,血圧の評価やその測定意義について,特に腎疾患との関連を中心に記載する.さらに血圧を規定する因子として重要な体液量についても概説する.

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Accumulating evidence has demonstrated that both SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1Ra) have protective effects in patients with diabetic kidney disease. Combination therapy with SGLT2i and GLP1Ra is commonly used in patients with type 2 diabetes (T2D). We previously reported that in combination therapy of SGLT2i and GLP1Ra, the effect on the renal composite outcome did not differ according to the preceding drug. However, it remains unclear how the initiation of combination therapy is associated with the renal function depending on the preceding drug. In this post hoc analysis, we analyzed a total of 643 T2D patients (GLP1Ra-preceding group, n = 331; SGLT2i-preceding group, n = 312) and investigated the differences in annual eGFR decline. Multiple imputation and propensity score matching were performed to compare the annual eGFR decline. The reduction in annual eGFR decline in the SGLT2i-preceding group (pre: −3.5 ± 9.4 mL/min/1.73 m²/year, post: −0.4 ± 6.3 mL/min/1.73 m²/year, p &amp;lt; 0.001), was significantly smaller after the initiation of GLP1Ra, whereas the GLP1Ra-preceding group tended to slow the eGFR decline but not to a statistically significant extent (pre: −2.0 ± 10.9 mL/min/1.73 m²/year, post: −1.8 ± 5.4 mL/min/1.73 m²/year, p = 0.83) after the initiation of SGLT2i. After the addition of GLP1Ra to SGLT2i-treated patients, slower annual eGFR decline was observed. Our data raise the possibility that the renal benefits—especially annual eGFR decline—of combination therapy with SGLT2i and GLP1Ra may be affected by the preceding drug.

DOI： 10.3389/fphar.2024.1358573

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1007/s10157-024-02486-7

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Other Link： https://link.springer.com/article/10.1007/s10157-024-02486-7/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1253/circj.CJ-23-0285

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A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered.

DOI： 10.1007/s13730-024-00855-5

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AIMS: High platelet-derived thrombogenicity during the acute phase of ST-segment elevation myocardial infarction (STEMI) is associated with poor outcomes; however, the associated factors remain unclear. This study aimed to examine whether acute inflammatory response after STEMI affects platelet-derived thrombogenicity. METHODS: This retrospective observational single-center study included 150 patients with STEMI who were assessed for platelet-derived thrombogenicity during the acute phase. Platelet-derived thrombogenicity was assessed using the area under the flow-pressure curve for platelet chip (PL-AUC), which was measured using the total thrombus-formation analysis system (T-TAS). The peak leukocyte count was evaluated as an acute inflammatory response after STEMI. The patients were divided into two groups: the highest quartile of the peak leukocyte count and the other three quartiles combined. RESULTS: Patients with a high peak leukocyte count (＞15,222/mm3; n=37) had a higher PL-AUC upon admission (420 [386-457] vs. 385 [292-428], p=0.0018), higher PL-AUC during primary percutaneous coronary intervention (PPCI) (155 [76-229] vs. 96 [29-170], p=0.0065), a higher peak creatine kinase level (4200±2486 vs. 2373±1997, p＜0.0001), and higher PL-AUC 2 weeks after STEMI (119 [61-197] vs. 88 [46-122], p=0.048) than those with a low peak leukocyte count (≤ 15,222/mm3; n=113). The peak leukocyte count after STEMI positively correlated with PL-AUC during primary PPCI (r=0.37, p＜0.0001). A multivariable regression analysis showed the peak leukocyte count to be an independent factor for PL-AUC during PPCI (β=0.26, p=0.0065). CONCLUSIONS: An elevated leukocyte count is associated with high T-TAS-based platelet-derived thrombogenicity during the acute phase of STEMI.

DOI： 10.5551/jat.64395

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DOI： 10.1038/s41440-023-01481-x

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BACKGROUND: Increasing physical activity improves glycemic control in patients with type 2 diabetes (T2D). Mobile health (mHealth) interventions have been proven to increase exercise, but engagement often fades with time. As the use of health behavior theory in mHealth design can increase effectiveness, we developed StepAdd, an mHealth intervention based on the constructs of social cognitive theory (SCT). StepAdd improves exercise behavior self-efficacy and self-regulation through the use of goal-setting, barrier-identifying, and barrier-coping strategies, as well as automatic feedback functions. A single-arm pilot study of StepAdd among 33 patients with T2D showed a large increase in step count (mean change of 4714, SD 3638 daily steps or +86.7%), along with strong improvements in BMI (mean change of -0.3 kg/m2) and hemoglobin A1c level (mean change of -0.79 percentage points). OBJECTIVE: In this study, we aim to investigate the efficacy and safety of StepAdd, an mHealth exercise support system for patients with T2D, via a large, long, and controlled follow-up to the pilot study. METHODS: This is a randomized, open-label, multicenter study targeting 160 patients with T2D from 5 institutions in Japan with a 24-week intervention. The intervention group will record daily step counts, body weight, and blood pressure using the SCT-based mobile app, StepAdd, and receive feedback about these measurements. In addition, they will set weekly step count goals, identify personal barriers to walking, and define strategies to overcome these barriers. The control group will record daily step counts, body weight, and blood pressure using a non-SCT-based placebo app. Both groups will receive monthly consultations with a physician who will advise patients regarding lifestyle modifications and use of the app. The 24-week intervention period will be followed by a 12-week observational period to investigate the sustainability of the intervention's effects. The primary outcome is between-group difference in the change in hemoglobin A1c values at 24 weeks. The secondary outcomes include other health measures, measurements of steps, measurements of other behavior changes, and assessments of app use. The trial began in January 2023 and is intended to be completed in December 2025. RESULTS: As of September 5, 2023, we had recruited 44 patients. We expect the trial to be completed by October 8, 2025, with the follow-up observation period being completed by December 31, 2025. CONCLUSIONS: This trial will provide important evidence about the efficacy of an SCT-based mHealth intervention in improving physical activities and glycemic control in patients with T2D. If this study proves the intervention to be effective and safe, it could be a key step toward the integration of mHealth as part of the standard treatment received by patients with T2D in Japan. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCT) jRCT2032220603; https://rctportal.niph.go.jp/en/detail?trial_id=jRCT2032220603. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53514.

DOI： 10.2196/53514

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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BACKGROUND: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is caused by mutations in the ubiquitin-activating enzyme1 (UBA1) gene and characterised by an overlap between autoinflammatory and haematologic disorders. CASE PRESENTATION: We reported a case of a 67-year-Japanese man receiving peritoneal dialysis (PD) who had recurrent aseptic peritonitis caused by the VEXAS syndrome. He presented with unexplained fevers, headache, abdominal pain, conjunctival hyperaemia, ocular pain, auricular pain, arthralgia, and inflammatory skin lesions. Laboratory investigations showed high serum C-reactive protein concentration and increased cell count in PD effluent. He was treated with antibiotics for PD-related peritonitis, but this was unsuccessful. Fluorine-18-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography images demonstrated intense FDG uptake in his left superficial temporal artery, nasal septum, and bilateral auricles. The working diagnosis was giant cell arteritis, and he was treated with oral prednisolone (PSL) 15 mg daily with good response. However, he was unable to taper the dose to less than 10 mg daily because his symptoms flared up. Since Tocilizumab was initiated, he could taper PSL dose to 2 mg daily. Sanger sequencing of his peripheral blood sample showed a mutation of the UBA1 gene (c.122 T > C; p.Met41Thr). We made a final diagnosis of VEXAS syndrome. He suffered from flare of VEXAS syndrome at PSL of 1 mg daily with his cloudy PD effluent. PSL dose of 11 mg daily relieved the symptom within a few days. CONCLUSIONS: It is crucial to recognise aseptic peritonitis as one of the symptoms of VEXAS syndrome and pay attention to the systemic findings in the patients.

DOI： 10.1186/s12882-024-03454-9

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Background and Objectives: Omega-3 fatty acids have potent lipid-lowering and antiplatelet effects; however, randomized controlled trials have yet to examine the effect of high-dose omega-3 fatty acid administration on peripheral artery disease (PAD) in hemodialysis patients with dyslipidemia. Therefore, this study aimed to evaluate the effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the ankle-brachial index (ABI) and remnant-like lipoprotein cholesterol (RLP-C) levels, which are indicators of PAD severity. Materials and Methods: Thirty-eight participants (mean age: 73.6 ± 12.7 years) were randomly assigned using stratified block randomization to either conventional therapy alone or conventional therapy supplemented with high-dose EPA/DHA (EPA: 1860 mg; DHA: 1500 mg) for a three-month intervention period. Patients in the conventional therapy alone group who opted to continue were provided with a low-dose EPA/DHA regimen (EPA: 930 mg; DHA: 750 mg) for an additional three months. The baseline and 3-month values for RLP-C, an atherogenic lipid parameter, and the ABI were recorded. Results: The results of the 3-month assessments revealed that the mean RLP-C changes were -3.25 ± 3.15 mg/dL and 0.44 ± 2.53 mg/dL in the EPA/DHA and control groups, respectively (p < 0.001), whereas the changes in the mean ABI values were 0.07 ± 0.11 and -0.02 ± 0.09 in the EPA/DHA and control groups, respectively (p = 0.007). In the EPA/DHA group, a significant negative correlation was found between the changes in RLP-C levels and the ABI (r = -0.475, p = 0.04). Additionally, the change in the RLP-C levels independently influenced the change in the ABI in the EPA/DHA group, even after adjusting for age, sex, and statin use (p = 0.042). Conclusions: Add-on EPA/DHA treatment improved the effectiveness of conventional therapy (such as statin treatment) for improving the ABI in hemodialysis patients with dyslipidemia by lowering RLP-C levels. Therefore, clinicians involved in dialysis should focus on RLP-C when considering residual cardiovascular disease risk in hemodialysis patients and should consider screening patients with elevated levels.

DOI： 10.3390/medicina60010075

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OBJECTIVES: Although ChatGPT was not developed for medical use, there is growing interest in its use in medical fields. Understanding its capabilities and precautions for its use in the medical field is an urgent matter. We hypothesized that differences in the amounts of information published in different medical fields would be proportionate to the amounts of training ChatGPT receives in those fields, and hence its accuracy in providing answers. STUDY DESIGN: A non-clinical experimental study. METHODS: We administered the Japanese National Medical Examination to GPT-3.5 and GPT-4 to examine the rates of accuracy and consistency in their responses. We counted the total number of documents in the Web of Science Core Collection per medical field and assessed the relationship with ChatGPT's accuracy. We also performed multivariate-adjusted models to investigate the risk factors for incorrect answers. RESULTS: For GPT-4, we confirmed an accuracy rate of 81.0 % and a consistency rate of 88.8 % on the exam; both showed improvement compared to those for GPT-3.5. A positive correlation was observed between the accuracy rate and consistency rate (R = 0.51, P < 0.001). The number of documents per medical field was significantly correlated with the accuracy rate in that medical field (R = 0.44, P < 0.05), with relatively few publications being an independent risk factor for incorrect answers. CONCLUSIONS: Checking consistency may help identify incorrect answers when using ChatGPT. Users should be aware that the accuracy of the answers by ChatGPT may decrease when it is asked about topics with limited published information, such as new drugs and diseases.

DOI： 10.1016/j.ijmedinf.2023.105283

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BACKGROUND AND AIM: Dysregulation of angiotensin II type 1 receptor-associated protein (ATRAP) expression in cardiovascular, kidney, and adipose tissues is involved in the pathology of hypertension, cardiac hypertrophy, atherosclerosis, kidney injury, and metabolic disorders. Furthermore, ATRAP is highly expressed in bone marrow-derived immune cells; however, the functional role of immune cell ATRAP in obesity-related pathology remains unclear. Thus, we sought to identify the pathophysiological significance of immune cell ATRAP in the development of visceral obesity and obesity-related metabolic disorders using a mouse model of diet-induced obesity. METHODS: Initially, we examined the effect of high-fat diet (HFD)-induced obesity on the expression of immune cell ATRAP in wild-type mice. Subsequently, we conducted bone marrow transplantation to generate two types of chimeric mice: bone marrow wild-type chimeric (BM-WT) and bone marrow ATRAP knockout chimeric (BM-KO) mice. These chimeric mice were provided an HFD to induce visceral obesity, and then the effects of immune cell ATRAP deficiency on physiological parameters and adipose tissue in the chimeric mice were investigated. RESULTS: In wild-type mice, body weight increase by HFD was associated with increased expression of immune cell ATRAP. In the bone marrow transplantation experiments, BM-KO mice exhibited amelioration of HFD-induced weight gain and visceral fat expansion with small adipocytes compared BM-WT mice. In addition, BM-KO mice on the HFD showed significant improvements in white adipose tissue metabolism, inflammation, glucose tolerance, and insulin resistance, compared with BM-WT mice on the HFD. Detailed analysis of white adipose tissue revealed significant suppression of HFD-induced activation of transforming growth factor-beta signaling, a key contributor to visceral obesity, via amelioration of CD206+ macrophage accumulation in the adipose tissue of BM-KO mice. This finding suggests a relevant mechanism for the anti-obesity phenotype in BM-KO mice on the HFD. Finally, transcriptome analysis of monocytes indicated the possibility of genetic changes, such as the enhancement of interferon-γ response at the monocyte level, affecting macrophage differentiation in BM-KO mice. CONCLUSION: Collectively, our results indicate that ATRAP in bone marrow-derived immune cells plays a role in the pathogenesis of visceral obesity. The regulation of ATRAP expression in immune cells may be a key factor against visceral adipose obesity with metabolic disorders.

DOI： 10.1016/j.metabol.2023.155706

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AIMS: This study aimed to clarify the renal influence of glucagon-like peptide 1 receptor agonists (GLP1Ras) with or without sodium-glucose co-transporter 2 inhibitors (SGLT2is) on Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively extracted 547 patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. The progression of albuminuria status and/or a ≥ 15% decrease in the estimated glomerular filtration rate (eGFR) per year was set as the renal composite outcome. Propensity score matching was performed to compare GLP1Ra-treated patients with and without SGLT2i. RESULTS: After matching, 186 patients in each group were compared. There was no significant difference of the incidence of the renal composite outcomes (17% vs. 20%, P = 0.50); however, the annual decrease in the eGFR was significantly smaller and the decrease in the urine albumin-to-creatinine ratio was larger in GLP1Ra-treated patients with the concomitant use of SGLT2is than in those without it (-1.1 ± 5.0 vs. -2.8 ± 5.1 mL/min/1.73 m2, P = 0.001; and -0.08 ± 0.61 vs. 0.05 ± 0.52, P = 0.03, respectively). CONCLUSION: The concomitant use of SGLT2i with GLP1Ra improved the annual decrease in the eGFR and the urine albumin-to-creatinine ratio in Japanese patients with T2DM.

DOI： 10.1097/XCE.0000000000000292

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The renin-angiotensin system (RAS) plays a crucial role in the regulation of blood pressure. Activation of the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) signaling pathway contributes to the pathogenesis of hypertension and subsequent organ damage. AT1R-associated protein (ATRAP) has been identified as an endogenous inhibitory protein of the AT1R pathological activation. We have shown that mouse Atrap (Atrap) represses various Ang II-AT1R-mediated pathologies, including hypertension in mice. The expression of human ATRAP (ATRAP) /Atrap can be altered in various pathological states in humans and mice, such as Ang II stimulation and serum starvation. However, the regulatory mechanisms of ATRAP/Atrap are not yet fully elucidated. MicroRNAs (miRNAs) are 21-23 nucleotides of small RNAs which post-transcriptionally repress gene expression. Single miRNA can act on hundreds of target mRNAs, and numerous miRNAs have been identified as the Ang II-AT1R signaling-associated disease phenotype modulator, but nothing is known about the regulation of ATRAP/Atrap. In the present study, we identified miR-125a-5p and miR-125b-5p as the evolutionarily conserved miRNAs that potentially act on ATRAP/Atrap mRNA. Further analysis revealed that miR-125a-5p and miR-125b-5p can directly repress both ATRAP and Atrap. In addition, the inhibition of miR-125a-5p/miR-125b-5p resulted in the suppression of the Ang II-AT1R signaling in mouse distal convoluted tubule (mDCT) cells. Taken together, miR-125a-5p/miR-125b-5p activates Ang II-AT1R signaling by the suppression of ATRAP/Atrap. Our results provide new insights into the potential approaches for achieving the organ-protective effects by the repression of the miR-125 family associated with the enhancement of ATRAP/Atrap expression.

DOI： 10.1016/j.jbc.2023.105478

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The progress in the research field of diabetic kidney disease (DKD) has been disturbed by the lack of reliable animal models. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R and selectively inhibits pathological AT1R signaling. In this study, we investigated whether overactivation of the renin-angiotensin system (RAS) through a combination of ATRAP deletion with Ang II stimulation developed a progressive DKD model in C57BL/6 mice, which are resistant to the development of kidney injury. Eight-week-old male systemic ATRAP-knockout mice on the C57BL/6 strain (KO) and their littermate wild-type mice (Ctrl) were divided into five groups: 1) Ctrl, 2) Ctrl-streptozotocin (STZ), 3) KO-STZ, 4) Ctrl-STZ-Ang II, and 5) KO-STZ-Ang II. Ang II was administered for 6 weeks from 4 weeks after STZ administration. At 10 weeks after STZ administration, mice were euthanized to evaluate kidney injuries. Neither ATRAP deletion alone nor Ang II stimulation alone developed a progressive DKD model in STZ-induced diabetic C57BL/6 mice. However, a combination of ATRAP deletion with Ang II stimulation accelerated the development of DKD as manifested by overt albuminuria, glomerular hypertrophy, podocyte loss, mesangial expansion, kidney interstitial fibrosis and functional insufficiency, concomitant with increased angiotensinogen and AT1R expression in the kidneys. In STZ-induced diabetic C57BL/6 mice that are resistant to the development of kidney injury, the combination of ATRAP deletion and Ang II stimulation accelerates the development of DKD, which may be associated with intrarenal RAS overactivation.

DOI： 10.1038/s41440-023-01496-4

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DOI： 10.1038/s41440-023-01508-3

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Background Contradictions between management modalities of type A acute aortic dissection (TAAAD) and ST-elevation-myocardial infarction (STEMI) may result in clinical catastrophe. Therefore, we aimed to explore which 2-dimensional echocardiography (2DE) findings are optimal for differentiating TAAAD from STEMI. Methods and Results This study included 340 patients with STEMI and 340 patients with TAAAD who underwent 2DE in the emergency department between 2012 and 2021. The proximal ascending aorta (PAA) diameter and other echocardiographic parameters were analyzed. PAA diameters were measured at 4 levels in the parasternal view: Valsalva, the sinotubular junction (STJ), the PAA at 1 cm above the STJ, and the PAA at 2 cm above the STJ. Receiver-operating characteristic curve analysis showed that Valsalva, STJ, PAA at 1 cm above the STJ, and PAA at 2 cm above the STJ were significant predictors of TAAAD (areas under the curve: 0.777, 0.924, 0.965, and 0.975, respectively; P<0.001) with the respective cutoff values of 39.4, 38.5, 39.8, and 41.2 mm. Multivariable analysis suggested that all 2DE parameters were significant predictors of TAAAD. Among the 2DE parameters examined, the incorporation of PAA at 2 cm above the STJ to clinical indicators exhibited the most significant diagnostic capability (C-statistics, 0.97; net reclassification improvement, 1.81; integrated discrimination improvement, 0.61). When only TAAAD with coronary malperfusion and STEMI were analyzed, the diagnostic utility of PAA at 1 cm above the STJ was evident (C-statistics, 0.99; net reclassification improvement, 1.79; integrated discrimination improvement, 0.67), with PAA at 2 cm above the STJ ranking second in diagnostic significance (C-statistics, 0.99; net reclassification improvement, 1.12; integrated discrimination improvement, 0.66). Conclusions PAA measurements were the most beneficial for diagnosing TAAAD in all 2DE findings and TAAAD from STEMI.

DOI： 10.1161/JAHA.123.029506

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We aim to assess the data of patients with hypertension in Kanagawa Prefecture, Japan, collected in 2021 that were provided by the Japan Medical Association Database of Clinical Medicine. Data collected in 2011 and 2014 by the Kanagawa Physicians Association were used for comparative analysis. The target blood pressure (BP) achievement rates for patients whose target office and home BP were <140/90 mmHg and <135/85 mmHg, respectively, were 72.5% and 75.8% in 2011, 66.0% and 68.5% in 2014, and 46.7% and 83.3% in 2021, respectively. The target office BP achievement rate in 2021 was significantly lower than those in 2011 and 2014 (p ≤ 0.009). In contrast, there was no significant difference and improvement of the achievement rates for patients whose target office and home BP were <130/80 mmHg and <125/75 mmHg, respectively, among the three surveys. After the Japanese Society of Hypertension 2019 Guidelines were released, the achievement rates for patients whose target BP was tightened were significantly lower than those for patients with unchanged target BP (office/home, p < 0.001/0.04). The proportion of the patients who achieved their office and home target BP using more than three drugs was 38.5% and 20.0%, respectively. In the present analysis, we unveiled the current problems encountered in the clinical management of hypertension in Japan. In particular, efforts should be focused on the management of patients that require strict BP control.

DOI： 10.1038/s41440-023-01366-z

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AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. METHODS AND RESULTS: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. CONCLUSION: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria.

DOI： 10.1093/ehjopen/oead098

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Publishing type：Research paper (scientific journal)   Publisher：SAGE Publications  

Aims

Combination therapy with sodium-glucose cotransporter inhibitors (SGLT2is) and GLP-1 receptor agonists (GLP1Ras) is now of interest in clinical practice. The present study evaluated the effects of the preceding drug type on the renal outcome in clinical practice.

Methods

We retrospectively extracted type 2 diabetes mellitus patients who had received both SGLT2i and GLP1Ra treatment for at least 1 year. A total of 331 patients in the GLP1Ra-preceding group and 312 patients in the SGLT2i-preceding group were ultimately analyzed. Either progression of the albuminuria status and/or a ≥30% decrease in the eGFR was set as the primary renal composite outcome. The analysis using propensity score with inverse probability weighting was performed for the outcome.

Results

The incidences of the renal composite outcome in the SGLT2i- and GLP1Ra-preceding groups were 28% and 25%, respectively, with an odds ratio [95% confidence interval] of 1.14 [0.75, 1.73] ( p = .54). A logistic regression analysis showed that the mean arterial pressure (MAP) at baseline, the logarithmic value of the urine albumin-to-creatinine ratio at baseline, and the change in MAP were independent factors influencing the renal composite outcome.

Conclusion

With combination therapy of SGLT2i and GLP1Ra, the preceding drug did not affect the renal outcome.

DOI： 10.1177/14791641231222837

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Language：Japanese   Publisher：(株)メジカルビュー社  

＜文献概要＞Ca拮抗薬は,ジヒドロピリジン系(dihydropyridine:DHP)と,非ジヒドロピリジン系[フェニルアルキルアミン(phenylalkylamine:PAA)系,ベンゾジアゼピン(benzothiazepine:BTZ)系]に分類される。DHPは降圧効果に優れ,薬効発揮までの時間が短く,適応患者が多いために広く使用されている。DHPの使い分けには,L型チャネルの遮断が基本作用ではあるが,どのDHPがN型やT型に作用するのかを把握しておく必要がある。Ca拮抗薬は狭心症合併患者,特に冠攣縮性狭心症にも有用性が認められる。非DHPは抗不整脈薬としても使用される。本稿ではCa拮抗薬の薬理作用と副作用について解説する。

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The renin-angiotensin system in the brain plays a pivotal role in modulating sympathetic nerve activity and contributes to the pathogenesis of hypertension. Angiotensin II (Ang II) type 1 receptor (AT1R)-associated protein (ATRAP) promotes internalization of AT1R while suppressing pathological overactivation of AT1R signaling. However, the pathophysiological function of ATRAP in the brain remains unknown. Therefore, this study aims to investigate whether ATRAP in the paraventricular nucleus (PVN) is involved in neurogenic hypertension pathogenesis in Ang II-infused rats. The ATRAP/AT1R ratio, which serves as an indicator of tissue AT1R hyperactivity, tended to decrease within the PVN in the Ang II group than in the vehicle group. This suggests an Ang II-induced hyperactivation of the AT1R signaling pathway in the PVN. Lentiviral vectors were generated to stimulate ATRAP expression. At 6 weeks of age, rats were microinjected with LV-Venus (Venus-expressing lentivirus) or LV-ATRAP (Venus-ATRAP-expressing lentivirus). The rats were then randomly divided into four groups: (1) Vehicle/LV-Venus, (2) Vehicle/LV-ATRAP, (3) Ang II/LV-Venus, and (4) Ang II/LV-ATRAP. Two weeks after microinjection, vehicle or Ang II was administered systemically for 2 weeks. In the Ang II/LV-ATRAP group, systolic blood pressure at 1 and 2 weeks following administration was significantly lower than that in the Ang II/LV-Venus group. Furthermore, urinary adrenaline levels tended to decrease in the Ang II/LV-ATRAP group than in the Ang II/LV-Venus group. These findings suggest that enhanced ATRAP expression in the PVN suppresses Ang II-induced hypertension, potentially by suppressing hyperactivation of the tissue AT1R signaling pathway and, subsequently, sympathetic nerve activity.

DOI： 10.1038/s41440-023-01480-y

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Sodium-glucose cotransporter 2 inhibitor (SGLT2-I) shows excellent antihypertensive effects in addition to its hypoglycemic effects. However, whether body mass index (BMI) affects the antihypertensive effect of SGLT2-I remains unknown. We investigated the impact of baseline BMI on the achievement of target blood pressure (BP) with SGLT2-I treatment in Japanese patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). We retrospectively evaluated 447 Japanese patients with T2DM and CKD treated with SGLT2-I for at least 1 year. The primary outcome was achieving the target BP (<130/80 mmHg) after SGLT2-I treatment. Patients were divided into two groups according to a baseline BMI of 29.1 determined by receiver operating characteristic analysis and analyzed in a cohort model with propensity score matching. In each group, 130 patients were compared by propensity score matching. The target BP achievement rate was significantly higher in the BMI < 29.1 group than in the BMI ≥ 29.1 group (34% and 21%, respectively, p = 0.03). The odds ratio for achieving the target BP in the BMI ≥ 29.1 group was 0.50 (95% confidence interval, 0.28-0.90, p = 0.02). The BMI < 29.1 group had significantly lower systolic and diastolic BPs after SGLT2-I treatment than the BMI ≥ 29.1 group. Only the BMI < 29.1 group was showed a significant decrease in the logarithmic albumin-to-creatinine ratio from baseline after SGLT2-I treatment. In patients with T2DM and CKD, baseline BMI was associated with the antihypertensive effects of SGLT2-I. Patients in the lower baseline BMI group were more likely to achieve the target BP after SGLT2-I treatment. Pretreatment BMI affects the antihypertensice effect of SGLT2 inhibirors in patients with T2DM and CKD.

DOI： 10.1038/s41440-023-01464-y

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DOI： 10.31662/jmaj.2023-0104

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DOI： 10.31662/jmaj.2023-0137

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AIM: To compare the therapeutic effects of glucose-dependent insulinotropic polypeptide (GIP)/ glucagon-like peptide-1 receptor agonists (GLP-1RAs) or GLP-1RAs in Japanese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: We systematically searched PubMed, MEDLINE, EMBASE, and the Cochrane Library up to July 2023. Randomized controlled trials (RCTs) that compared GLP-1RAs or GIP/GLP-1RAs in Japanese patients with T2D were selected. A network meta-analysis was conducted to indirectly compare the treatments, focusing on efficacy in reducing glycated haemoglobin (HbA1c) levels and body weight (BW). RESULTS: A total of 18 RCTs were included in this analysis. Tirzepatide 15 mg showed the most significant reduction in HbA1c levels and BW compared with subcutaneous semaglutide 1.0 mg and oral semaglutide 14 mg (HbA1c: mean difference [95% confidence interval] -0.52 [-0.96; -0.08] and - 1.23 [-1.64; -0.81]; BW: -5.07 [-8.28; -1.86] and -6.84 [-8.97; -4.71], respectively). Subcutaneous semaglutide showed a superior reduction in HbA1c compared with oral semaglutide. Both subcutaneous and oral semaglutide were more effective than conventional GLP-1RAs, such as dulaglutide, liraglutide and lixisenatide. CONCLUSIONS: Among Japanese patients with T2D, tirzepatide showed the greatest effectiveness in reducing HbA1c levels and inducing weight loss. The study provides evidence to guide GLP-1RA treatment strategies in Japanese patients with T2D.

DOI： 10.1111/dom.15312

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AIM: Low-density lipoprotein cholesterol (LDL-C) level reduction is highly effective in preventing the occurrence of a cardiovascular event. Contrariwise, an inverse association exists between LDL-C levels and prognosis in some patients with cardiovascular diseases-the so-called "cholesterol paradox." This study aimed to investigate whether the LDL-C level on admission affects the long-term prognosis in patients who develop acute coronary syndrome (ACS) and to examine factors associated with poor prognosis in patients with low LDL-C levels. METHODS: We enrolled 410 statin-naïve patients with ACS, whom we divided into low- and high-LDL-C groups based on an admission LDL-C cut-off (obtained from the Youden index) of 122 mg/dL. Endothelial function was assessed using the reactive hyperemia index 1 week after statin initiation. The primary composite endpoint included all-cause death, as well as myocardial infarction and ischemic stroke occurrences. RESULTS: During a median follow-up period of 6.1 years, 76 patients experienced the primary endpoint. Multivariate Cox regression analysis revealed that patients in the low LDL-C group had a 2.3-fold higher risk of experiencing the primary endpoint than those in the high LDL-C group (hazard ratio, 2.34; 95% confidence interval, 1.29-4.27; p=0.005). In the low LDL-C group, slow gait speed (frailty), elevated chronic-phase high-sensitivity C-reactive protein levels (chronic inflammation), and endothelial dysfunction were significantly associated with the primary endpoint. CONCLUSIONS: Patients with low LDL-C levels at admission due to ACS had a significantly worse long-term prognosis than those with high LDL-C levels; frailty, chronic inflammation, and endothelial dysfunction were poor prognostic factors.

DOI： 10.5551/jat.64368

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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BACKGROUND: Pulmonary hypertension (PH) has recently been described as a complex clinical syndrome affecting multiple organ systems, including the heart, lungs, and skeletal muscle, each of which plays an important role in exercise capacity. However, the relationship between exercise capacity and skeletal muscle abnormalities in patients with PH has not been fully elucidated. METHODS: We retrospectively analysed the exercise capacity and measures of skeletal muscle of 107 patients with PH without left heart disease (mean age 63 ± 15 years, 32.7% males, n = 30/6/66/5 in the clinical classification Group 1/3/4/5). RESULTS: Sarcopenia, low appendicular skeletal muscle mass index, low grip strength, and slow gait speed, determined by international criteria, were found in 15 (14.0%), 16 (15.0%), 62 (57.9%), and 41 (38.3%) patients, respectively. The mean 6-min walk distance of all patients was 436 ± 134 m and was independently associated with sarcopenia (standardised β = -0.292, p < 0.001). All patients with sarcopenia showed reduced exercise capacity defined as 6-min walk distance <440 m. Multivariable logistic regression analysis showed that each of the components of sarcopenia was associated with reduced exercise capacity (adjusted odds ratio and 95% confidence interval of appendicular skeletal muscle mass index: 0.39 [0.24-0.63] per 1 kg/m2, p = 0.006, grip strength: 0.83 [0.74-0.94] per 1 kg, p = 0.003, and gait speed: 0.31 [0.18-0.51] per 0.1 m/s, p < 0.001). CONCLUSIONS: Sarcopenia and its components are associated with reduced exercise capacity in patients with PH. A multifaceted evaluation may be important in the management of reduced exercise capacity in patients with PH.

DOI： 10.1016/j.ijcard.2023.06.006

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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Patients with primary aldosteronism (PA) have a higher risk of cardiovascular disease (CVD) than essential hypertension due to underlying hyperaldosteronism. However, the association between high plasma aldosterone concentrations (PACs) and diurnal blood pressure (BP) variation has not been fully elucidated. Because abnormal ambulatory blood pressure monitoring (ABPM) profiles are associated with increased CVD risk, we investigated the association between PACs and the ABPM profile in 36 patients with PA diagnosed by confirmatory tests who underwent adrenal venous sampling (AVS). The clinical parameters were measured during hospitalization for AVS. The dietary salt intake of hospitalized patients was controlled at 6 g/day. During AVS, blood samples were collected from the inferior vena cava before and 1 h after adrenocorticotropic hormone (ACTH) stimulation to measure the PACs. The post-stimulation PAC had a significant negative correlation with nocturnal BP dipping rates (R = -0.387, p = 0.020), whereas pre-stimulation PAC did not (R = -0.217, p = 0.204). The nocturnal BP dipping rates were significantly lower in the high PAC group (PAC higher than the median) than low PAC group (PAC lower than the median) (p = 0.009). Multiple regression analysis revealed that high PAC was an independent factor contributing to low nocturnal BP dipping rates (β = -0.316, p = 0.038). In conclusion, in patients with PA, hyperaldosteronism is associated with nocturnal hypertension, which is an important risk factor for CVD. Additionally, ACTH stimulation may improve the sensitivity of PACs as a clinical indicator of nocturnal hypertension.

DOI： 10.1038/s41440-023-01325-8

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DOI： 10.1038/s41440-023-01338-3

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DOI： 10.1038/s41440-023-01252-8

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGERNATURE  

Primary aldosteronism is the most frequent secondary hypertensive disease and is characterized by an elevated risk for cardiovascular disease. The current standard treatments are adrenalectomy and/or administration of mineralocorticoid receptor blockers, both of which are effective at ameliorating hypertension via intervention for hyperaldosteronism. However, both of these approaches have side effects and contraindications, and mineralocorticoid receptor blockers also have limited preventive efficacy against cardiovascular events. Recently, in vitro experiments have shown that aldosterone regulation is closely related to abdominal fat accumulation and that there is crosstalk between aldosterone and visceral fat tissue accumulation. We previously reported that this interaction was clinically significant in renal dysfunction; however, its effects on the heart remain unclear. Here, we analyzed data from 49 patients with primary aldosteronism and 29 patients with essential hypertension to examine the potential effect of the interaction between the ratio of visceral-to-subcutaneous fat tissue volume and the plasma aldosterone concentration on echocardiographic indices, including the tissue Doppler-derived E/e' ratio. A significant interaction was found in patients with primary aldosteronism (p < 0.05), indicating that patients with the combination of a high plasma aldosterone concentration and high visceral-to-subcutaneous fat ratio show an increased E/e' ratio, which is a well-known risk factor for future cardiovascular events. Our results confirm the clinical importance of the interaction between aldosterone and abdominal fat tissue, suggesting that an improvement in the visceral-to-subcutaneous fat ratio may be synergistically and complementarily effective in reducing the elevated risk of cardiovascular disease in patients with primary aldosteronism when combined with conventional therapies for reducing aldosterone activity.

DOI： 10.1038/s41440-023-01170-9

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AIMS: Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta-analysis to investigate the effects of SGLT2-Is, MRAs and their combination on albuminuria in type 2 DM. METHODS: We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2-Is, MRAs + SGLT2-Is, or a placebo in patients with type 2 DM with a urinary albumin-creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. RESULTS: This meta-analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2-Is and MRAs was associated with lower albuminuria compared with the use of SGLT2-Is, MRAs, or the placebo alone [mean difference (95% CI): -34.19 (-27.30; -41.08), -32.25 (-24.53; -39.97) and -65.22 (-57.97; -72.47), respectively]. Treatment with SGLT2-Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): -31.03 (-28.35; -33.72) and -32.97 (-29.68; -36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2-Is. Sensitivity analyses showed similar results. CONCLUSION: Combination therapy with SGLT2-Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2-Is or MRAs alone.

DOI： 10.1111/dom.14976

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DOI： 10.1038/s41440-023-01241-x

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Considering the prevalence of obesity and global aging, the consumption of a high-protein diet (HPD) may be advantageous. However, an HPD aggravates kidney dysfunction in patients with chronic kidney disease (CKD). Moreover, the effects of an HPD on kidney function in healthy individuals are controversial. In this study, we employed a remnant kidney mouse model as a CKD model and aimed to evaluate the effects of an HPD on kidney injury under conditions of non-CKD and CKD. Mice were divided into four groups: a sham surgery (sham) + normal diet (ND) group, a sham + HPD group, a 5/6 nephrectomy (Nx) + ND group and a 5/6 Nx + HPD group. Blood pressure, kidney function and kidney tissue injury were compared after 12 weeks of diet loading among the four groups. The 5/6 Nx groups displayed blood pressure elevation, kidney function decline, glomerular injury and tubular injury compared with the sham groups. Furthermore, an HPD exacerbated glomerular injury only in the 5/6 Nx group; however, an HPD did not cause kidney injury in the sham group. Clinical application of these results suggests that patients with CKD should follow a protein-restricted diet to prevent the exacerbation of kidney injury, while healthy individuals can maintain an HPD without worrying about the adverse effects.

DOI： 10.3390/ijms24097778

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The incidence of heart failure and chronic kidney disease is increasing, and many patients develop both diseases. Angiotensin receptor-neprilysin inhibitor (ARNI) is a promising therapeutic candidate for both diseases. ARNI has demonstrated superior cardioprotective effects compared with renin-angiotensin system inhibitors (RAS-Is) in large clinical trials such as the PARADIGM-HF (Prospective Comparison of ARNI With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. It has also been suggested that ARNI can provide renoprotective effects beyond those of RAS-Is in patients with HF. ARNI might have beneficial effects on the kidneys because of its ability to improve cardiac function in patients with heart failure and affect renal hemodynamics by enhancing the effects of hormones such as natriuretic peptide. In contrast, in the PARADIGM-HF trial, ARNI was associated with more albuminuria compared with RAS-I; thus, it is unclear whether long-term ARNI therapy has renoprotective effects. Additionally, ARNI did not provide renoprotective effects beyond RAS-I in patients with chronic kidney disease in the UK HARP-III (United Kingdom Heart and Renal Protection-III) trial. In other words, the patient population in which ARNI is more renoprotective than RAS-I might be limited. Collectively, ARNI may have renoprotective effects in addition to cardioprotective effects, but the evidence to date is applicable only to heart failure. Theoretically, given the molecular mechanism of ARNI, it could also be renoprotective in conditions such as nephrosclerosis, which has low risks of albuminuria and reduced kidney perfusion, but the evidence for such effects is lacking. Further research is needed to clarify whether ARNI therapy is an acceptable treatment strategy for renal protection.

DOI： 10.1161/JAHA.122.029565

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BACKGROUNDS: Recently, there has been increasing awareness that bleeding may lead to adverse outcomes. Endothelial dysfunction is associated with increased risk of cardiovascular and bleeding events. This study aimed to investigate the association of endothelial dysfunction with major bleeding and specific causes of death in addition to major adverse cardiovascular events in patients with acute coronary syndrome. METHODS: This single-centre retrospective observational study was conducted at a tertiary-care hospital; patients with acute coronary syndrome were included between June 2010 and November 2014 (median follow-up, 6.1 years). The reactive hyperaemia index was assessed before their discharge; reactive hyperaemia index <1.67 was defined as endothelial dysfunction. The main outcomes were the incidence of major bleeding, all-cause death, cardiovascular death, non-cardiovascular death, resuscitated cardiac arrest, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation for heart failure. RESULTS: Among the included 674 patients with acute coronary syndrome, 264 (39.2%) had endothelial dysfunction. Multivariable Cox-hazard analyses revealed an independent predictive value of endothelial dysfunction for major bleeding (hazard ratio 2.29, 95% confidence interval 1.17-4.48, P = 0.016) and major adverse cardiovascular events (hazard ratio 2.04, 95% confidence interval 1.43-2.89, P < 0.001). The endothelial dysfunction group patients had a 2.5-fold greater risk of cardiovascular death; however, no association was found with non-cardiovascular death. CONCLUSION: Endothelial dysfunction assessed using reactive hyperaemia index predicted future major cardiovascular event as well as major bleeding and cardiovascular death in patients with acute coronary syndrome.

DOI： 10.1016/j.ijcard.2023.01.079

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Background Chronic kidney disease-mineral and bone disorder (CKD-MBD), nutritional status, and uremia management have been emphasized for bone management in hemodialysis patients. Nevertheless, valuable data on the importance of muscle mass in bone management are limited, including whether conventional management alone can prevent osteoporosis. Thus, the importance of muscle mass and strength, independent of the conventional management in osteoporosis prevention among hemodialysis patients, was evaluated. Methods Patients with a history of hemodialysis 6 months or longer were selected. We assessed the risk for osteoporosis associated with calf circumference or grip strength using multivariable adjustment for indices of CKD-MBD, nutrition, and dialysis adequacy. Moreover, the associations between bone mineral density (BMD), calf circumference, grip strength, and bone metabolic markers were also evaluated. Results A total of 136 patients were included. The odds ratios (95% confidence interval) for osteoporosis at the femoral neck were 1.25 (1.04-1.54, P < 0.05) and 1.08 (1.00-1.18, P < 0.05) per 1 cm shorter calf circumference or 1 kg weaker grip strength, respectively. Shorter calf circumference was significantly associated with a lower BMD at the femoral neck and lumbar spine (P < 0.001). Weaker grip strength was also associated with lower BMD at the femoral neck (P < 0.01). Calf circumference or grip strength was negatively correlated with bone metabolic marker values. Conclusion Shorter calf circumference or weaker grip strength was associated with osteoporosis risk and lower BMD among hemodialysis patients, independent of the conventional therapies.

DOI： 10.1007/s10157-022-02308-8

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：Japanese   Publisher：日本臨床分子医学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

BACKGROUND: We aimed to investigate the impact of a fourth dose of BNT162b2 vaccine (Comirnaty®, Pfizer-BioNTech) on anti-SARS-CoV-2 (anti-S IgG) antibody titers in patients receiving hemodialysis (HD) and healthcare workers (HCWs). METHODS: A multi-institutional retrospective study at five dialysis clinics in Japan was conducted using 238 HD patients and 58 HCW controls who received four doses of the BNT162b2 mRNA vaccine. Anti-S IgG titers were measured at 1, 3, and 6 months after the second dose, at 1 and 5/6 months after the third dose, and at 1 month after the fourth dose of vaccine. RESULTS: The log anti-S IgG titers of the HD patients after the second vaccination were significantly lower than those of the control group, but equalized 1 month after the third vaccination: 9.94 (95% CI 9.82-10.10) vs. 9.81 (95% CI 9.66-9.96), (P = 0.32). In both groups, the fold-increase in anti-S IgG titers was significantly lower after the fourth dose than after the third dose of vaccine. In addition, there was a strong negative correlation between antibody titers 1 month after the fourth vaccination and antibody titers immediately before the vaccination. In both groups, the waning rate of anti-S IgG titers from the post-vaccination peak level after the third vaccine dose was significantly slower than that after the second dose. CONCLUSIONS: These findings suggest that the humoral immune response was blunted after the fourth dose of the conventional BNT162b2 vaccine. However, multiple vaccinations could extend the window of humoral immune protection.

DOI： 10.1007/s10157-023-02342-0

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Other Link： https://link.springer.com/article/10.1007/s10157-023-02342-0/fulltext.html

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DOI： 10.1038/s41440-023-01251-9

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Language：Japanese   Publisher：(有)科学評論社  

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Language：English   Publisher：(一社)日本循環器学会  

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This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

DOI： 10.1038/s41598-023-29653-2

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In Japan, the standard method for measuring plasma aldosterone concentration (PAC) for primary aldosteronism (PA) diagnosis was changed from radioimmunoassay (RIA) to a novel chemiluminescent enzyme immunoassay (CLEIA). The purpose of this study is to simulate the possible impact of the change on PA diagnosis. This retrospective study assessed 2,289 PA patients. PACs measured by conventional RIA were transformed to estimated PACs (CLEIA) as follows: RIA (pg/mL) = 1.174 × CLEIA (pg/mL) + 42.3. We applied the estimated PAC (CLEIA) to the conventional cut-off of aldosterone-to-renin activity ratio ≥200 for screening and captopril challenge test (CCT) and PAC ≥60 pg/mL for saline infusion test (SIT). Application of the estimated PAC to screening and confirmatory tests decreased the number of PA diagnoses by 36% (743/2,065) on CCT and 52% (578/1,104) on SIT (discrepant cases). Among the discrepant cases, 87% (548/628) of CCT and 87% (452/522) of SIT were bilateral on adrenal venous sampling (AVS). Surgically treatable aldosterone-producing adenomas (APAs) were observed in 6% (36/579) and 5% (23/472) of discrepant cases on CCT and SIT, respectively; most were characterized by hypokalemia and/or adrenal nodule on CT imaging. Application of the PAC measured by the novel CLEIA to conventional cut-offs decreases the number of PA diagnoses. Although most discrepant cases were bilateral on AVS, there are some APA cases that were characterized by hypokalemia and/or adrenal tumor on CT. Further studies which evaluate PACs measured by both RIA and CLEIA for each patient are needed to identify new cut-offs for PAC measured by CLEIA.

DOI： 10.1507/endocrj.EJ22-0585

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DOI： 10.1007/s10157-023-02323-3

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：(一社)日本内科学会  

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BACKGROUND: Although weight loss in heart failure (HF) is a detrimental condition known as cachexia, weight gain caused by fluid retention should also be considered harmful. However, studies with sufficient number of patients examining the impact of weight change and its interval on in-hospital mortality in HF have not been conducted thus far. We sought to elucidate the association of weight change with in-hospital mortality in patients with HF. METHODS: This retrospective observational study used data from the Diagnosis Procedure Combination database, a nationwide inpatient health claims database in Japan. In total, 48 234 patients repeatedly hospitalized for HF (median 82 [74-87] years; 46.4% men) between 2010 and 2018 were included. Weight change was derived from body weight at the first and second admissions. RESULTS: The median weight change and interval between two hospitalizations were -3.1 [-8.3 to -1.8] % and 172 [67-420] days, with 66.9% of overall cohort experiencing any weight loss. As a result of multivariable-adjusted logistic regression analysis, weight loss <-5.0% and weight gain >+5.0% were associated with increased in-hospital mortality (adjusted odds ratio [OR] [95% confidence interval]: 1.46 [1.31-1.62], P < 0.001 and 1.23 [1.08-1.40], P = 0.002, respectively) whereas mild weight loss and gain of 2.0-5.0% were not (OR [95% confidence interval]: 0.96 [0.84-1.10], P = 0.57 and 1.07 [0.92-1.25], P = 0.37, respectively), in comparison with patients with a stable weight (fluctuating no more than -2.0% to +2.0%) used as a reference. Restrictive cubic spline models adjusted for multiple background factors illustrated that higher mortality in patients with weight loss was observed across all subgroups of the baseline body mass index (<18.5, 18.5-24.9 and ≥25.0 kg/m2 ). In patients with short (<90 days) and middle (<180 days) intervals between the two hospitalizations, both weight loss and weight gain were associated with high mortality, whereas the association between weight gain and high mortality was attenuated in those with longer intervals. CONCLUSIONS: Both weight loss and weight gain in patients with repeated hospitalization for HF were associated with high in-hospital mortality, especially weight loss and short/middle-term weight gain. Such patients should be treated with caution in a setting of repeated hospitalization for HF.

DOI： 10.1002/jcsm.13170

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DOI： 10.1038/s41598-022-25880-1

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DOI： 10.1038/s41440-022-01022-y

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BACKGROUND: Making lifestyle changes is an essential element of abdominal obesity (AO) reduction. To support lifestyle modification and self-management, we developed an information and communication technology-based self-management system-DialBeticsLite-with a fully automated dietary evaluation function for the treatment of AO. OBJECTIVE: The objective of this study was to evaluate the preliminary efficacy and feasibility of DialBeticsLite among Japanese office workers with AO. METHODS: A 2- to 3-month prospective single-arm pilot intervention study was designed to assess the effects of the intervention using DialBeticsLite. The information and communication technology system was composed of 4 modules: data transmission (body weight, blood pressure, blood glucose, and pedometer count); data evaluation; exercise input; and food recording and dietary evaluation. Eligible participants were workers who were aged ≥20 years and with AO (waist circumference ≥85 cm for men and ≥90 cm for women). Physical parameters, blood tests, nutritional intake, and self-care behavior were compared at baseline and after the intervention. RESULTS: A total of 48 participants provided completed data for analysis, which yielded a study retention rate of 100%. The average age was 46.8 (SD 6.8) years, and 92% (44/48) of participants were male. The overall average measurement rate of DialBeticsLite, calculated by dividing the number of days with at least one measurement by the number of days of the intervention, was 98.6% (SD 3.4%). In total, 85% (41/48) of the participants reported that their participation in the study helped them to improve their lifestyle. BMI, waist circumference, and visceral fat area decreased significantly after the intervention (P<.001). In addition, the daily calorie intake reduced significantly (P=.02). There was a significant improvement in self-care behavior in terms of exercise and diet (P=.001). CONCLUSIONS: Using DialBeticsLite was shown to be a feasible and potentially effective method for reducing AO by providing users with a motivational framework to evaluate their lifestyle behaviors.

DOI： 10.2196/40366

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AIMS: Both sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular (CV) event in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, little evidence pertains to the benefits of their combined use. METHODS: We systematically searched the PubMed, MEDLINE, EMBASE, and Cochrane Library databases through July 2022. We selected randomized controlled trials comparing SGLT-2 inhibitors, MRAs, or SGLT-2 inhibitor + MRA combination therapy, with placebo in patients with T2D and CKD. We performed a network meta-analysis to indirectly compare the treatments. The primary outcome was a composite of CV events. RESULTS: Eight studies were selected with 36,186 patients. The primary outcome was significantly improved in the combination therapy group compared with the other groups (RR [95% CI]; vs SGLT-2 inhibitors, 0.76 [0.60; 0.96]; vs MRAs, 0.66 [0.53; 0.82]; vs placebo, 0.58 [0.47; 0.73]). Additionally, the combination therapy was associated with a considerable reduction in the risk of hyperkalemia (RR vs MRA, 0.43 [0.23; 0.79]). CONCLUSION: Combination of SGLT-2 inhibitors and MRAs potentially reduced CV events compared with SGLT-2 inhibitors or MRAs alone. This combination may be a candidate treatment strategy for patients with T2D and CKD.

DOI： 10.1016/j.diabres.2022.110161

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DOI： 10.1038/s41440-022-01106-9

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Language：Japanese   Publisher：(一社)日本アフェレシス学会  

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BACKGROUND: Rapidly progressive, extensive myocardial injury/infarction (RPEMI) beyond the concept of wave-front phenomenon can be observed even when achieving timely reperfusion; however, the pathogenesis of RPEMI remains unknown. This retrospective study investigated clinical and lesion characteristics of RPEMI, focusing on culprit-lesion morphology (CLM). METHODS: Among patients with extensive anterior-wall ST-segment elevation myocardial infarction due to proximal left anterior descending artery lesions who had reperfusion within 3 hours of symptom onset, 60 patients undergoing both intravascular ultrasound and cardiac magnetic resonance imaging were enrolled. Myocardial injury/infarction before reperfusion therapy was assessed by QRS scores at hospitalization electrocardiogram, and the extent of myocardial injury/infarction was evaluated by cardiac magnetic resonance imaging, which measured area at risk, infarct size, myocardial salvage index, microvascular obstruction, and left ventricular ejection fraction. RPEMI was defined as lower left ventricular ejection fraction (less median value) with microvascular obstruction. RESULTS: Despite comparable onset-to-door and onset-to-reperfusion times and area at risk, patients with RPEMI showed higher QRS scores at hospitalization (5 [4.3-6] versus 3 [2-4], P<0.001) and infarct size (26.5±9.1 versus 20.4±10.5%, P=0.04), and a tendency toward lower myocardial salvage index (0.27±0.14 versus 0.36±0.20, P=0.10) compared with those without. Patients with versus without RPEMI more frequently observed specific CLM on intravascular ultrasound, characterized by the combination of vulnerable plaques, plaque ruptures, and/or large thrombi. When stratified by CLM-score composed of these 3 criteria, higher CLM-scores were or tended to be associated with higher QRS scores and incidence of RPEMI. In multivariate analyses including no-reflow phenomenon and final coronary-flow deterioration, increased CLM-score (≥2) was independently associated with high QRS scores and RPEMI (odd ratio 11.25 [95% CI, 2.43-52.00]; P=0.002). CONCLUSIONS: Vulnerable CLM was a consistent determinant of advanced myocardial injury/infarction both before and after reperfusion therapy and may play a pivotal role in the development of RPEMI.

DOI： 10.1161/CIRCIMAGING.122.014497

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Kidney fibrosis is a common pathway that leads to chronic kidney disease. Angiotensin II type-1 receptor (AT1R)-associated protein (ATRAP) was originally identified as an AT1R-binding protein. Previously, we reported that systemic knockout of ATRAP exacerbates kidney fibrosis in aged mice. Although these effects of ATRAP appeared to be AT1R-independent actions, the molecular mechanism remains poorly understood. To elucidate the molecular mechanism of ATRAP independent of AT1R, we explored novel ATRAP-interacting proteins. Mass spectrometric analysis of the immunoprecipitants of a Flag-tagged ATRAP complex revealed 376 candidate proteins that potentially interact with ATRAP. Gene ontology analysis revealed that proteins related to vesicle trafficking, membrane transport, and many membrane proteins, including transferrin receptor 1 (TfR1), were enriched. Because TfR1 promotes cellular iron uptake and iron is a key factor involved in kidney fibrosis, we focused on TfR1 and confirmed that it interacts with ATRAP. In addition, our findings revealed that enhanced ATRAP expression decreased cell-surface TfR1 expression without altering the overall cellular TfR1 expression levels. Furthermore, enhanced ATRAP expression attenuated cellular iron levels. Together, our results highlight the role of ATRAP as a suppressor of TfR1 that functions by facilitating TfR1 internalization, which affects iron metabolism and oxidative stress signaling.

DOI： 10.1038/s41598-022-22343-5

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AIMS: Reduced skeletal muscle mass is a major component of sarcopenia, associated with impaired exercise capacity and poor prognosis in patients with heart failure (HF). Measurement of skeletal muscle mass by dual-energy X-ray absorptiometry may be affected by fluid retention, typically in the patients' lower extremities. The aim of the present study was to elucidate the association between upper and lower extremity skeletal muscle mass (USM and LSM) and all-cause mortality in hospitalized patients with HF, after discharge. METHODS: This was a single-centre observational cohort study of 418 patients (59% were men) admitted with a diagnosis of HF (71 ± 13 years), with a left ventricular ejection fraction of 39 ± 16%. USM and LSM were measured by dual-energy X-ray absorptiometry with patients in a stable state after decongestion therapy. RESULTS: The USM and LSM were 5.29 ± 1.18 and 13.78 ± 3.20 kg for men and 3.37 ± 0.68 and 9.19 ± 1.80 kg for women. A positive correlation was obtained between USM and LSM with mid-upper arm circumference (r = 0.684, P < 0.001) and calf circumference (r = 0.822, P < 0.001), respectively. During a median follow-up of 37 months, 92 (22.0%) of the 418 patients died. A Kaplan-Meier analysis revealed that sex-specific quartiles of USM/height2 and LSM/height2 were associated with all-cause mortality (both P < 0.001 by the log-rank test). In Cox models adjusted by age, sex, creatinine, haemoglobin, NYHA class, and height2 , the hazard ratio with 95% confidence intervals for all-cause mortality was 0.557 [0.393-0.783] (P < 0.001) for USM per 1 kg, and 0.783 [0.689-0.891] (P < 0.001) for LSM per 1 kg. The receiver-operator-characteristic curve analysis showed a comparable area under the curve between the USM/height2 and LSM/height2 (0.557 vs. 0.568, P = 0.562) in predicting all-cause mortality. The ratio of USM to LSM was significantly lower in 37 patients with residual leg oedema than in the 360 patients without oedema (36.1% vs. 38.1%, P = 0.004), suggesting the influence of oedema on measured LSM. CONCLUSIONS: Both USM and LSM had a prognostic implication on mortality after discharge in HF, even though LSM may have been affected by leg oedema. These findings indicate that clinicians should not ignore a patient's USM or LSM in the prognostication of patients with HF.

DOI： 10.1002/ehf2.14195

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DOI： 10.1253/circj.CJ-22-0417

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Language：Japanese   Publisher：(NPO)日本高血圧学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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The cardiovascular and renal protective effects of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) and glucagon-like peptide 1 receptor agonists (GLP-1Ras) are enhanced by low/controlled blood pressure (BP). However, the BP-lowering efficacy of SGLT-2is and GLP-1Ras have not been compared directly. We compared the rates of achieving target BP with SGLT-2i and GLP-1Ra treatments in Japanese patients with type 2 diabetes mellitus (T2DM). This retrospective study included 384 SGLT-2i- and 160 GLP-1Ra-treated patients with BP > 130/80 mmHg before treatment. Inverse probability weighting methods using propensity scores were used in this study. The integrated odds ratios (OR) for BP control rates were calculated and clinical changes were analyzed using a generalized linear model. SGLT-2i treatment resulted in significantly higher BP control rates than that in the GLP-1Ra treatment (integrated OR = 2.09 [1.80, 2.43]). Compared with GLP-1Ra, SGLT-2i treatment demonstrated significantly larger decreases in diastolic BP, mean arterial pressure, and body weight (- 3.8 mmHg, P = 0.006; - 4.1 mmHg, P = 0.01; and - 1.5 kg, P = 0.008, respectively) and increased annual estimated glomerular filtration rate (eGFR; 1.5 mL/min/1.73 m2/year, P = 0.04). In T2DM patients with poorly controlled BP, compared with GLP-1Ra, SGLT-2i treatment significantly improved BP management and increased eGFR.

DOI： 10.1038/s41598-022-20313-5

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The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than essential hypertension. However, associated factors of comorbid AF and cardiovascular events in PA patients after PA treatment remain unclear. This nationwide registration study included PA patients ≥20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3654 patients with PA were included at the time of analysis. Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent factors associated with AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to older age, duration of hypertension, body mass index and chronic kidney disease as independent prognostic factors for cardiovascular events after PA treatment. Incidence of cardiovascular events were significantly lower in PA patients with AF than AF patients from the Fushimi registry during follow-up after adjusting age, sex and systolic blood pressure. Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension and appropriate PA treatment.

DOI： 10.1038/s41371-022-00753-2

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BACKGROUND: The access site for primary percutaneous coronary intervention (PCI) for patients with ST-elevation myocardial infarction (STEMI) recently shifted from femoral to radial. However, few real-world data on Japanese patients exist. METHODS: To elucidate the clinical selection and impact of the access site in STEMI patients, we analyzed a Japanese observational prospective multicenter registry of acute myocardial infarction (K-ACTIVE: Kanagawa ACuTe cardIoVascular rEgistry) in 2015 to 2021. Data were analyzed in the entire population and a propensity score-matched population adjusted for confounding factors. Major adverse cardiac event (MACE) was defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Bleeding Academic Research Consortium (BARC) type 3 or 5 was used to assess bleeding events. MACE plus BARC type 3 or 5 bleeding were considered composite events. Clinical outcomes were followed for 30 days. RESULTS: The 6802 STEMI patients included 4786 patients with radial access (70.3 %) and 2016 with femoral access (29.7 %). Femoral access tended to be selected for more severe conditions than radial access. The median door-to-device time in the radial access group was significantly shorter than the femoral access group in the entire population (75 min versus 79 min, p < 0.01). After propensity score matching (each group, n = 1208), the incidence of MACE tended to be lower in the radial access group [risk ratio (RR) 0.83, 95 % confidence interval (CI) 0.63-1.09, p = 0.17]. The incidence of BARC 3 or 5 bleeding was significantly less in the radial access group (RR 0.47, 95%CI 0.23-0.97, p = 0.04). The incidence of composite events was significantly less in the radial access group (RR 0.74, 95%CI 0.57-0.96, p = 0.02). CONCLUSION: In STEMI patients undergoing primary PCI, in comparison to femoral access, radial access reduced composite events in the entire population and the matched population, through a reduction in MACE and BARC 3 or 5 bleeding.

DOI： 10.1016/j.jjcc.2022.09.001

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BACKGROUND: Immune checkpoint inhibitors (ICIs) are becoming widely used for novel cancer treatments. Immune-related adverse events, including cardiac toxicity, are frequently observed following immune checkpoint inhibitor (ICI) use. However, little is known regarding the association between ICIs initiation and hypertension in cancer patients. METHODS: A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and Web of Science Core Collection. The risk of hypertension associated with ICI initiation in randomized controlled trials (RCTs) was evaluated. Hypertension was categorized according to the Common Terminology Criteria for Adverse Events. The odds ratios of grades I to V and grades III to V hypertension were calculated using a random-effects meta-analysis. RESULTS: Thirty-two RCTs (n=19 810 cancer patients) were included. At a median follow-up of 36 months, the median overall survival was 15 months in the ICI group. ICI initiation was not significantly associated with hypertension (grades I-V: odds ratio, 1.12 [95% CI, 0.96-1.30]; grades III-V: odds ratio, 0.95 [95% CI, 0.78-1.16]). Additionally, no significant differences in hypertension risk were evident in ICI combination therapies with various drugs, including anti-VEGF (vascular endothelial growth factor) agents. In a subgroup analysis based on clinical setting (placebo RCT versus nonplacebo RCT), there were discrepancies between the results obtained with different methodologies, with patients in the nonplacebo RCTs having higher grades I-V hypertension (I2=88.6%, P for heterogeneity=0.003). CONCLUSIONS: ICI initiation was not associated with short-term risk of hypertension in cancer patients, and the association was similar regardless of concomitant treatment with other anticancer drugs.

DOI： 10.1161/HYPERTENSIONAHA.122.19865

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DOI： 10.1016/j.ekir.2022.09.005

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Context: Adrenocorticotropin (ACTH) loading is used to increase the success rate of adrenal vein sampling (AVS). Objective: We aimed to determine the effect of intraprocedural cortisol measurement (ICM) on ACTH-stimulated AVS (AS-AVS) owing to a lack of reliable data on this topic. Methods: This multicenter, retrospective, observational study took place in 28 tertiary centers in Japan. Among 4057 patients enrolled, 2396 received both basal AVS (B-AVS) and AS-AVS and were divided into 2 groups according to whether ICM was used. The effect of ICM on AS-AVS was measured. Results: In patients who underwent both AVS procedures, the ICM group had significantly higher success rates for both B-AVS and AS-AVS than the non-ICM group did. However, the probability of failure of AS-AVS after a successful B-AVS and the probability of success of AS-AVS after a failed B-AVS were not significantly different in the 2 groups. For subtype diagnosis, propensity-score matching revealed no significant difference between the 2 groups, and the discrepancy rate between B-AVS and AS-AVS for subtype diagnosis was also not significantly different. Conclusion: ICM significantly increased the success rate of B-AVS and AS-AVS in protocols in which both AVS procedures were performed and had no effect on subtype diagnosis. However, in protocols in which both AVS procedures were performed, the results suggest ICM may not be necessary when performing AS-AVS if ICM is used only when B-AVS is performed. Our study suggests that ICM during AVS plays an important role and should be recommended.

DOI： 10.1210/jendso/bvac104

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AIMS/INTRODUCTION: After the first coronavirus disease 2019 state of emergency announcement, there was an increase in stress that might have affected the self-management of patients with type 2 diabetes mellitus. This study identified the changes in clinical findings and stress among patients with type 2 diabetes mellitus, and investigated the characteristics of patients who experienced an increase in blood pressure (BP) after the announcement. MATERIALS AND METHODS: Retrospectively, we scrutinized 310 patients with type 2 diabetes mellitus who were treated by the Sagamihara Physicians Association. After the announcement, 164 and 146 patients showed an increase (ΔBP >0 group) and decrease in BP (ΔBP ≤0 group), respectively. The propensity score matching method was used to compare the differences in clinical findings and stress-related questionnaire responses between the two groups. RESULTS: After the announcement, 47% of patients experienced an increase in daily stress. Furthermore, 17% and 36% reported worsening dietary intake and a decrease in exercise, respectively. More patients reported that their dietary and salt intake had worsened in the ΔBP >0 group than in the ΔBP ≤0 group (9% vs 20%, P = 0.02, and 3% vs 10%, P = 0.04, respectively). Additionally, both systolic and diastolic BP measured in the office were significantly increased (P = 0.02 and P = 0.03, respectively); however, systolic BP measured at home significantly decreased (P = 0.01). The total stress scores were higher in the ΔBP >0 group than in the ΔBP ≤0 group (0.05 ± 2.61 and 0.93 ± 2.70, respectively, P = 0.03). CONCLUSIONS: An increase in stress and, particularly, worsening dietary and salt intake were noted among patients with type 2 diabetes mellitus who experienced an increase in BP after the state of emergency announcement.

DOI： 10.1111/jdi.13813

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Language：Japanese   Publisher：(一社)日本心臓病学会  

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OBJECTIVE: This study aimed to investigate the possible influence of arterial stiffness assessed by the cardio-ankle vascular index (CAVI) on chronic-phase left ventricular dysfunction in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: A total of 208 consecutive patients with first STEMI (age, 64 ± 11 years; 86% men) who underwent reperfusion therapy within 12 h of onset were enrolled. We analysed arterial stiffness by measuring CAVI in a stable phase after admission and performed two-dimensional echocardiography at baseline and 7 months' follow-up. Subsequently, we assessed left ventricular global longitudinal strain (LV-GLS) to evaluate left ventricular function. A total of 158 (75.9%) patients underwent baseline cardiac magnetic resonance (CMR). We estimated left ventricular infarct size by measuring peak levels of creatine kinase-myocardial band (CK-MB), and CMR-late gadolinium enhancement (LGE). RESULTS: On the basis of the median CAVI value, the patients were allocated into high CAVI (CAVI ≥ 8.575) and low CAVI (CAVI < 8.575) groups. The groups showed no statistically significant differences in LV-GLS at baseline (-13.5% ± 3.1 vs. -13.9% ± 2.7%, P  = 0.324). However, LV-GLS was significantly worse in the high CAVI group than in the low-CAVI group at 7 months (-14.0% ± 2.9 vs. -15.6% ± 3.0%, P  < 0.001). Stratified by CAVI and peak CK-MB or LGE, the four groups showed significant differences in LV-GLS at 7 months after STEMI (both P  < 0.001). Multivariate linear regression analysis with the forced inclusion model showed that CAVI was an independent predictor of LV-GLS at 7 months ( P  = 0.015). CONCLUSION: CAVI early after STEMI onset was significantly associated with chronic-phase LV-GLS. In addition, combining CAVI with CK-MB or LGE improves its predictive ability for evaluation of chronic-phase LV-GLS. Thus, the arterial stiffness assessment by CAVI was an important factor related to chronic-phase left ventricular dysfunction after the first STEMI.

DOI： 10.1097/HJH.0000000000003165

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BACKGROUND: The optimal endpoint after balloon angioplasty remains poorly defined. This study aimed to characterize post-balloon angioplasty anatomical and physiological indexes by quantitative flow ratio (QFR) and to compare their prognostic impacts on long-term clinical outcomes. METHODS: This retrospective study included 106 lesions from 106 patients who underwent percutaneous coronary interventions with drug-coated-balloon (n = 69) or plain-old-balloon-angioplasty (n = 37). Analyses measured minimum lumen diameter (MLD) and percent diameter stenosis (%DS) as anatomical indexes; QFR of target vessel (QFR-vessel) and QFR-gradient (ΔQFR between proximal and distal segments of the lesion) as physiological indexes. Primary endpoint was target lesion revascularization (TLR) after the index procedure. RESULTS: TLR occurred in 21 (20 %) lesions. TLR group showed significantly smaller QFR-vessel (0.79 ± 0.12 vs. 0.85 ± 0.12, p = 0.03), as well as greater QFR-gradient (0.12 ± 0.07 vs. 0.04 ± 0.03, p < 0.0001) at post-procedure compared with non-TLR group. The percentage of angiographically significant dissection was also more frequently observed in TLR group compared with non-TLR group (47.6 % vs. 14.1 %, p < 0.0001 for log-rank). In the multivariate analysis, angiographically significant dissection and QFR-gradient at post-procedure was significantly associated with TLR. In the receiver-operating characteristics curve analysis, the area under the curve for predicting post-procedural TLR was significantly greater for QFR-gradient than for MLD and residual %DS (p < 0.0001 for MLD and p = 0.0003 for residual %DS at post-procedure). The best cut-off value of post-procedural QFR-gradient for predicting TLR was 0.08. CONCLUSIONS: Post-procedural QFR-gradient across the lesion was a statistically independent and stronger predictor of TLR, compared with anatomical indexes.

DOI： 10.1016/j.jjcc.2022.07.007

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A 76-year-old female who had a history of endovascular treatment (EVT) for her left superficial femoral artery with endovascular stent grafts [VIABAHN (W. L. Gore & Associates, Inc., DE, USA)] suddenly experienced intermittent claudication of her left leg. Angiography revealed total occlusion of previous stent grafts, and a thrombus aspiration catheter was used after crossing the guidewire. Since retrograde angiography using a thrombus aspiration catheter revealed a large residual thrombus at the distal edge of the previous stent even after several thrombus aspirations, biopsy forceps for intestinal endoscopes [Radial Jaw (Boston Scientific, MA, USA)] were successfully used to remove that thrombus. After balloon inflation under distal protection, angiography revealed a large residual thrombus at her left common femoral artery with a flow limiting of her deep femoral artery. Again, biopsy forceps were successfully used to remove that thrombus. In this case series, we reported a total of 11 cases which underwent EVT using biopsy forceps for intestinal endoscopes [Radial Jaw (Boston Scientific, MA, USA)]. Of the 11 cases, eight underwent EVT using biopsy forceps for thrombus removal, two underwent calcification removal in severely calcified lesions, and one underwent removal of a detached guidewire. There were no major adverse limb events (MALEs) except for one patient who underwent major amputation after EVT. One MALE occurred independently of biopsy forceps use because biopsy forceps were used only to remove the detached wire. Biopsy forceps for intestinal endoscopes were clinically useful and safe for EVT.

DOI： 10.1007/s12928-021-00831-1

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Since the onset of the coronavirus disease 2019 (COVID-19) pandemic, the possible roles of renin-angiotensin system (RAS) inhibitors in COVID-19 have been debated as favorable, harmful, or neutral. Angiotensin-converting enzyme 2 (ACE2) not only is the entry route of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but also triggers a major mechanism of COVID-19 aggravation by promoting tissue RAS dysregulation, which induces a hyperinflammatory state in several organs, leading to lung injury, hematological alterations, and immunological dysregulation. ACE inhibitors and angiotensin II type-1 receptor blockers (ARBs) inhibit the detrimental hyperactivation of the RAS by SARS-CoV-2 and increase the expression of ACE2, which is a counter-regulator of the RAS. Several studies have investigated the beneficial profile of RAS inhibitors in COVID-19; however, this finding remains unclear. Further prospective studies are warranted to confirm the role of RAS inhibitors in COVID-19. In this review, we summarize the potential effects of RAS inhibitors that have come to light thus far and review the impact of RAS inhibitors on COVID-19.

DOI： 10.1038/s41440-022-00922-3

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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Language：English   Publisher：(一社)日本心血管インターベンション治療学会  

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Language：Japanese   Publisher：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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Language：Japanese   Publisher：日本肺高血圧・肺循環学会・日本小児肺循環研究会  

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A recent report stated that patients with primary aldosteronism who remain renin suppressed during mineralocorticoid receptor antagonist treatment might have a higher risk of developing cardiovascular disease than those with unsuppressed renin activity. We retrospectively investigated the incidence of composite cardiovascular disease and risk factors for cardiovascular disease in 1115 Japanese patients with primary aldosteronism treated with mineralocorticoid receptor antagonists. The median follow-up period was 3.0 years, and the incidence of cardiovascular events was very low (2.1%) throughout 5 years of follow-up. Changes in plasma renin activity from before to after mineralocorticoid receptor antagonist treatment were divided into three groups based on tertile, low, intermediate, and high plasma renin activity change groups, with incidences of cardiovascular disease events of 2.1%, 0.5%, and 3.7%, respectively. Multivariate Cox regression analysis revealed age (adjusted hazard ratio, 1.07; 95% confidence interval, [1.02-1.12]) and body mass index (adjusted hazard ratio, 1.13 [1.04-1.23]) as independent risk factors for cardiovascular disease. The high plasma renin activity change group had significantly higher cardiovascular disease risk with mineralocorticoid receptor antagonist treatment than the intermediate plasma renin activity change group (adjusted hazard ratio, 5.71 [1.28-25.5]). These data suggest that a high change in renin level after mineralocorticoid receptor antagonist treatment may not necessarily predict a better prognosis of cardiovascular disease in patients with primary aldosteronism.

DOI： 10.1038/s41440-022-00960-x

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BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is shown to prevent severe illness and death in hemodialysis (HD) patients, but the immune response to vaccines is reduced in this population. This study compared SARS-CoV-2 spike protein antibody titers between HD patients and healthy controls in Japan for up to 6 months following vaccination. METHODS: A multi-institutional retrospective study at five clinics in Japan was conducted using 412 HD patients and 156 healthy controls who received two doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Anti-SARS-CoV-2 spike protein S1 IgG antibody titers were measured at 1, 3, and 6 months after the second dose. The attenuation speed was calculated as slope (i.e., -β) using a linear mixed-effects model toward the log-transformed antibody titers. RESULTS: The HD group had significantly lower month 1 antibody titers (Ab-titer-1) than the controls, and these remained lower through month 6 (95% CI: 2617.1 (1296.7, 5240.8) vs. 7285.4 (4403.9, 11,000.0) AU/mL at Ab-titer-1, and 353.4 (178.4, 656.3) vs. 812.0 (498.3, 1342.7) AU/mL at Ab-titer-6 (p < 0.001, respectively)). Lower log Ab-titer-1 levels in the HD group were significantly associated with a lower log Ab-titer-6 (0.90 [0.83, 0.97], p < 0.001). The -β values in the HD patients and healthy controls were -4.7 ± 1.1 and -4.7 ± 1.4 (year-1), respectively. CONCLUSION: SARS-CoV-2 spike protein antibody titers were significantly lower in HD patients than in healthy controls at 1 (peak) and 6 months after the second vaccination. Low peak antibody titers contributed to low 6-month antibody titers.

DOI： 10.1007/s10157-022-02243-8

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BACKGROUND: Identifying predictive factors for coronavirus disease 2019 (COVID-19) is crucial for risk stratification and intervention. Kidney dysfunction contributes to the severity of various infectious diseases. However, the association between on-admission kidney dysfunction and the clinical outcome in COVID-19 patients is unclear. METHODS: This study was a multicenter retrospective observational cohort study of COVID-19 patients, diagnosed by polymerase chain reaction. We retrospectively analyzed 500 COVID-19 patients (mean age: 51 ± 19 years) admitted to eight hospitals in Japan. Kidney dysfunction was defined as a reduced estimated glomerular filtration rate (< 60 mL/min/1.73 m2) or proteinuria (≥ 1 + dipstick proteinuria) on admission. The primary composite outcome included in-hospital death, extracorporeal membrane oxygenation, mechanical ventilation (invasive and noninvasive methods), and intensive care unit (ICU) admission. RESULTS: Overall, 171 (34.2%) patients presented with on-admission kidney dysfunction, and the primary composite outcome was observed in 60 (12.0%) patients. Patients with kidney dysfunction showed higher rates of in-hospital death (12.3 vs. 1.2%), mechanical ventilation (13.5 vs. 4.0%), and ICU admission (18.1 vs. 5.2%) than those without it. Categorical and multivariate regression analyses revealed that kidney dysfunction was substantially associated with the primary composite outcome. Thus, on-admission kidney dysfunction was common in COVID-19 patients. Furthermore, it correlated significantly and positively with COVID-19 severity and mortality. CONCLUSIONS: On-admission kidney dysfunction was associated with disease severity and poor short-term prognosis in patients with COVID-19. Thus, on-admission kidney dysfunction has the potential to stratify risks in COVID-19 patients.

DOI： 10.1007/s10157-022-02240-x

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DOI： 10.1016/j.atherosclerosis.2022.04.024

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BACKGROUND: The clinical incidence and impact of atrial fibrillation (AF) in Japanese acute myocardial infarction (AMI) patients is not fully understood. METHODS: To elucidate the clinical incidence and impact of AF on in-hospital mortality in AMI patients, we analyzed a Japanese observational prospective multicenter registry of acute myocardial infarction (K-ACTIVE: Kanagawa ACuTe cardIoVascular rEgistry), which spans 2015 to 2019. A major adverse cardiac event (MACE) was defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke. For assessing bleeding events, Bleeding Academic Research Consortium (BARC) type 3 or 5 was used. MACE plus BARC type 3 or 5 bleeding were considered as composite events. The clinical outcomes were followed for 1 year. RESULTS: The total of 5059 patients included 531 patients with AF (10.5%) and 4528 patients with sinus rhythm (SR; 89.5%). AF patients were significantly older and tended to have more comorbidities than SR patients. Oral anticoagulation therapy (OAC) was used in 44% of AF patients while single antiplatelet therapy was selected for 52% of patients with OAC. Crude in-hospital mortality was significantly greater in AF patients than in SR patients (10.4%, 5.0%, respectively, p < 0.01). The multivariate analysis was adjusted for age, sex, diabetes, hypertension, hemodialysis, smoking, previous MI, body mass index, Killip classification, out of hospital cardiac arrest, and OAC. In-hospital mortality was still significantly greater in AF patients than in SR patients in the logistic regression analysis [adjusted odds ratio 2.02 (1.31-3.14)]. AF was an independent risk factor for MACE and composite events in the Cox proportional hazards model [adjusted risk ratio (ARR) 1.91 (1.36-2.69), p < 0.01; ARR 1.72 (1.25-2.36), p < 0.01]. In contrast, AF was not an independent risk factor for bleeding [ARR 1.71 (0.79-3.71), p = 0.18]. CONCLUSION: In Japanese AMI patients, AF was often observed and was associated with worse MACE but not worse bleeding.

DOI： 10.1016/j.jjcc.2022.02.007

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Language：Japanese   Publisher：高尿酸血症・メタボリックシンドロームリサーチフォーラム  

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Background: The role of left ventricular (LV) mechanical dispersion estimated after an ST elevation acute myocardial infarction (STEMI) remains unclear. Methods: The study participants were 208 consecutive patients (152 men, age = 72 years) presenting with STEMI for the first time who underwent primary percutaneous coronary intervention (PCI) within 12 h of STEMI onset. Within 48 h of PCI (mean = 24 h), 2D and 3D speckle-tracking echocardiography were performed. The global longitudinal strain (GLS) was calculated using 3D (3D-GLS) and 2D (2D-GLS) speckle tracking. Mechanical dispersion was defined using the standard deviation (SD) of the time to regional peak longitudinal strain (LS) for all 16 segments for both 2D-STE and 3D-STE (2D-LS-SD, 3D-LS-SD). Infarct size was estimated by Tc99m-sestamibi as the total area of < 50% of the uptake area at 2 weeks. The patients were followed up for a longer period of time (median118months) and checked for major adverse cardiac events (MACE: cardiac death, heart failure). Results: During follow-up, 55 patients experienced MACE. The cut-off values were determined using receiver operating characteristic curves. The multivariate analysis revealed that a 3D-LS-SD > 56.7 ms was a significant predictor of MACEs (hazard ratio = 1.991, 95% confidence interval 1.033-3.613, p = 0.03), but 2D-LS-SD > 58.1 ms was not an independent predictor of MACEs (hazard ratio = 1.577, 95% confidence interval 0.815-3.042, p = 0.1). Furthermore, the combination of 3D-GLS and 3D-LS-SD had accurate predictability for MACE, as shown by the Kaplan-Meier curves (log rank, χ2 = 94.1, p < 0.0001). Conclusions: LV mechanical dispersion besides 3D-GLS assessed by 3D-STE immediately after PCI can predict long-term prognosis.

DOI： 10.1016/j.ijcha.2022.101028

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A 78-year-old man suffering from epigastric discomfort presented with an initial electrocardiogram showing complete right bundle branch block (RBBB) and ST-segment depression continuing to positive symmetrical T waves in leads V2 to V4, suggestive of de Winter's pattern. Emergent coronary angiography demonstrated 2-vessel disease with 90% stenosis in the proximal segment of the left anterior descending artery (LAD) with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow, and 75% in the mid portion and 90% in the distal portion of the right coronary artery, without collateral flow to LAD. A drug-eluting stent was deployed at the proximal LAD, and the flow of the diagonal branch deteriorated to TIMI grade 1 flow on the final angiogram. De Winter's pattern temporarily disappeared, and the procedure was finished. However, when the patient was admitted to the coronary care unit, de Winter's pattern emerged again with less severe epigastric discomfort. Subsequently, chest X-ray showed pulmonary edema in both lungs. Repeat angiography revealed acute stent thrombosis of LAD with TIMI grade 1 flow. De Winter's pattern with the combination of RBBB can be observed not only on admission but also at the time of occurrence of stent thrombosis. <Learning objective: De Winter's pattern reflects thrombotic occlusion of a large coronary artery without ST-segment elevation, and can be observed not only on admission but also at the time of occurrence of stent thrombosis. Positive T waves of de Winter's pattern in the right to mid precordial leads suggest acute thrombotic occlusion of left anterior descending artery, even in the presence of right bundle branch block.>.

DOI： 10.1016/j.jccase.2022.01.006

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BACKGROUND: The aim of this study was to create a risk scoring model to differentiate obstructive coronary artery (CA) from CA spasm in the etioology of acute coronary syndrome (ACS).Methods and Results: We included 753 consecutive patients with ACS without persistent ST-segment elevation (p-STE). The exclusion criteria were: (1) out-of-hospital cardiac arrest; (2) cardiogenic shock; (3) hemodialysis; (4) atrial fibrillation/flutter; (5) severe valvular disease; (6) no coronary angiography; (7) non-obstructive coronary artery without "definite" vasospastic angina definition; and/or (8) missing data. From the multivariate logistic regression analysis for prediction of obstructive CA, an integer score of 2 to each 0.5 increment in odds ratio was given, and values were divided into quartiles according to the total score. The scores were as follows: age >70 years (6 points), non-STE myocardial infarction (9 points), diabetes mellitus (5 points), B-type natriuretic peptide >90 pg/mL (7 points), neutrophil to lymphocyte ratio >2 (5 points), and high-density lipoprotein cholesterol <50 mg/dL (5 points). CA spasm-induced ACS occurred in 50.0% in Quartile 1 (total score: 0-13), 20.5% in Quartile 2 (total score: 14-19), 4.9% in Quartile 3 (total score: 20-26), and 2.2% in Quartile 4 (total score: 27-37) (P<0.001), indicating that a total score of <20 was a potential clinical indicator of CA spasm-induced ACS. CONCLUSIONS: CA spasm-induced ACS should be suspected if a total score of <20, and a spasm provocation test was being considered.

DOI： 10.1253/circj.CJ-22-0096

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Patients with pulmonary hypertension (PH) suffer from poor exercise tolerance due to impaired oxygenation and/or reduced cardiac output. However, the relationship between exercise tolerance and physical function remains unclear. The purpose of this study was to investigate the relationship between exercise tolerance and physical function in patients with PH. A total of 94 patients without left heart disease (61.3 ± 14.7 years old, 69.1% females, 22/8/60/4 patients with Group 1/3/4/5 PH) were retrospectively analysed. Physical function was measured using muscle strength (grip strength, knee extension muscle strength), balance function (one-leg standing time), and gait speed within 7 days of cardiac catheterization. Exercise tolerance was measured using the 6-min walking distance (6-MWD). A total of 194 6-MWD measurements and the corresponding physical function were evaluated in 94 patients. Multivariable linear regression analysis using adaptive-LASSO methods indicated that the World Health Organization functional classification, pulmonary vascular resistance, mixed venous oxygen saturation, grip strength, and gait speed were independently associated with the 6-MWD. Low grip strength (< 28 kg for males and < 18 kg for females; adjusted odds ratio and 95% confidence interval: 2.06 [1.30-3.26], p = 0.002), and slow gait speed (< 1.0 m/s for both sexes; 13.33 [3.61-49.19], p < 0.001) were independent predictors of poor exercise tolerance (6-MWD < 440 m) in a logistic regression analysis. Grip strength and gait speed as measures of physical function, pulmonary vascular resistance, and mixed venous oxygen saturation were associated with exercise tolerance in patients with PH without left heart disease.

DOI： 10.1007/s00380-022-02091-2

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BACKGROUND: The role of left atrial (LA) function in the long-term prognosis of ST-elevation acute myocardial infarction (STEMI) is still unclear.Methods and Results: Percutaneous coronary intervention (PCI) was performed in 433 patients with the first episode of STEMI within 12 h of onset. The patients underwent echocardiography 24 h after admission. LA reservoir strain and other echocardiographic parameters were analyzed. Follow up was performed for up to 10 years (mean duration, 91 months). The primary endpoint was major adverse cardiovascular events (MACE): cardiac death or hospitalization due to heart failure (HF). MACE occurred in 90 patients (20%) during the follow-up period. Multivariate Cox hazard analyses showed LA reservoir strain, global longitudinal strain (GLS), age and maximum B-type natriuretic peptide (BNP) were the significant predictors of MACE. Kaplan-Meier curves demonstrated that LA reservoir strain <25.8% was a strong predictor (Log rank, χ2=76.7, P<0.0001). Net reclassification improvement (NRI) demonstrated that adding LA reservoir strain had significant incremental effect on the conventional parameters (NRI and 95% CI: 0.24 [0.11-0.44]) . When combined with GLS >-11.5%, the patients with LA reservoir strain <25.8% were found to be at extremely high risk for MACE (Log rank, χ2=126.3, P<0.0001). CONCLUSIONS: LA reservoir strain immediately after STEMI onset was a significant predictor of poor prognosis in patients, especially when combined with GLS.

DOI： 10.1253/circj.CJ-21-0907

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AIMS/INTRODUCTION: We previously reported that sodium-glucose cotransporter 2 inhibitor (SGLT2i) treatment was associated with an improvement of the albumin-to-creatinine ratio in Japanese patients with type 2 diabetes mellitus and chronic kidney disease. The present study clarified how concomitant insulin treatment (IT) with SGLT2i therapy influences the renal composite outcome (RCO). MATERIALS AND METHODS: We retrospectively evaluated 624 Japanese patients with type 2 diabetes mellitus and chronic kidney disease who underwent SGLT2i treatment. The renal composite outcome was set as progression of the stage of albuminuria or a ≥15% decrease in the estimated glomerular filtration rate per year. We developed a cohort model of patients managed with and without IT (Ins [+], Ins [-]) using propensity score matching methods. Furthermore, all patients in our study population were stratified into quintiles according to their propensity score. RESULTS: The incidence of the RCO was in Ins (+) patients significantly higher than that in Ins (-) (P = 0.033). The estimated hazard ratio for the RCO was 1.55 (P = 0.035) in Ins (+) patients. The change in the estimated glomerular filtration rate and albumin-to-creatinine ratio in the groups was not statistically significant. The analysis, which was based on the quintiles, showed a statistically significant difference between the Ins (+) and Ins (-) groups (P = 0.01); the odds ratio for the RCO in patients managed with IT was 2.20 (P = 0.01). CONCLUSIONS: Concomitant administration of IT with SGLT2is influenced the RCO in Japanese patients with type 2 diabetes mellitus and chronic kidney disease. We might need to consider the influence of concomitant agents on the renoprotective effects of SGLT2i therapy.

DOI： 10.1111/jdi.13825

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Although activation of the renin-angiotensin system and of its glomerular components is implicated in the pathogenesis of diabetic nephropathy, the functional roles of the tubular renin-angiotensin system with AT1 receptor signaling in diabetic nephropathy are unclear. Tissue hyperactivity of the renin-angiotensin system is inhibited by the angiotensin II type 1 receptor-associated protein ATRAP, which negatively regulates receptor signaling. The highest expression of endogenous ATRAP occurs in the kidney, where it is mainly expressed by tubules but rarely in glomeruli. Here, we found that hyperactivation of angiotensin II type 1 receptor signaling in kidney tubules exacerbated diabetic glomerular injury in a mouse model of streptozotocin-induced diabetic nephropathy. These phenomena were accompanied by decreased expression of CD206, a marker of alternatively activated and tissue-reparative M2 macrophages, in the kidney tubulointerstitium. Additionally, adoptive transfer of M2- polarized macrophages into diabetic ATRAP-knockout mice ameliorated the glomerular injury. As a possible mechanism, the glomerular mRNA levels of tumor necrosis factor-α and oxidative stress components were increased in diabetic knockout mice compared to non-diabetic knockout mice, but these increases were ameliorated by adoptive transfer. Furthermore, proximal tubule-specific ATRAP downregulation reduced tubulointerstitial expression of CD206, the marker of M2 macrophages in diabetic mice. Thus, our findings indicate that tubular ATRAP-mediated functional modulation of angiotensin II type 1 receptor signaling modulates the accumulation of tubulointerstitial M2 macrophages, thus affecting glomerular manifestations of diabetic nephropathy via tubule-glomerular crosstalk.

DOI： 10.1016/j.kint.2022.01.031

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A 69-year-old woman was referred for upgrading implantable cardioverter defibrillator (ICD) to cardiac resynchronization therapy defibrillator (CRT-D) because of symptomatic heart failure due to dilated cardiomyopathy. Her electrocardiogram showed left bundle branch block and echocardiography showed severe left ventricular dysfunction. Venography confirmed the presence of persistent left superior vena cava (PLSVC), and occlusion of innominate vein and the coronary sinus (CS) ostium. We tried to insert the left ventricular (LV) lead through the PLSVC. Because the PLSVC was narrow, there was concern that insertion of the guiding catheter through the PLSVC might cause vascular damage. Therefore, we planned to implant the LV lead without a guiding catheter. Although the LV lead did not advance to the CS due to the acute angle, using a second wire (buddy wire system), the tip of the first wire was trapped by an inflated balloon delivered by a second wire (anchor balloon technique). This technique allowed us to reinforce the support of the other wire. The LV lead was easily advanced along with the fixed first wire and was delivered to the lateral vein of the CS. Thus, we successfully performed minimally invasive implantation of an LV lead through a PLSVC approach. <Learning objective: The double wire (buddy wire) technique and anchor balloon technique are effective options for implantation of a left ventricular lead through a persistent left superior vena cava in cardiac resynchronization therapy.>.

DOI： 10.1016/j.jccase.2021.11.009

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(株)ライフ・サイエンス  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本透析医学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Language：Japanese   Publisher：(一社)日本腎臓学会  

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Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

DOI： 10.1507/endocrj.EJ21-0508

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BACKGROUND: Tolvaptan (TLV) is reported to improve diuretic effects in patients with chronic kidney disease (CKD) when furosemide (FUR) is not sufficiently effective. However, it is not clear whether TLV addition is effective for advanced CKD patients with heart failure. METHODS: An open-label, parallel-group randomized trial was performed. The subjects were 33 patients with CKD stage G3-G5 who had fluid overload despite taking 20-100 mg/day FUR. They were divided into two groups: a group administered 15 mg/day TLV plus their original FUR dose for 7 days (TLV group), and a group administered 120-200 mg/day FUR (i.e., 100 mg/day over their previous dose) for 7 days (FUR group). RESULTS: The mean change in urine volume was significantly higher in the TLV group compared to the FUR group (637 ml vs 119 ml; p < 0.05). The difference was greater when the urine osmolality before treatment was high. Serum creatinine was increased only in the FUR group. The incidence of worsening renal function (WRF) was significantly lower in the TLV group (18.8% vs 58.8%; p < 0.05). Serum sodium decreased significantly in the FUR group, but did not change in the TLV group. CONCLUSIONS: In patients with advanced CKD with fluid overload, the addition of TLV achieved a significantly higher urine volume with less adverse effects on renal function compared with increasing the dose of FUR. The efficacy and safety of TLV were higher in patients who had higher urine osmolality and lower serum sodium before treatment. CLINICAL TRIAL REGISTRATION: UMIN000014763.

DOI： 10.1007/s10157-022-02224-x

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INTRODUCTION: Air bubbles in the dialysis circuit are rarely visible after automatic priming; however, they are often visible after the needles are manually connected to the circuit. To prevent this issue, we thought to prime needles with a circuit at automatic priming by the hemodialysis machine. In order to achieve this idea, we designed and manufactured a novel capped needle to connect the needles to the extracorporeal circuit before the automatic priming of the hemodialysis machine. This study investigated the effectiveness of this novel capped needle and compared it with the conventional method for preventing air bubble contamination. METHODS: We tested novel capped needles ten times to evaluate whether the dialysis machine works appropriately and removes air bubbles even with the attached capped needle. Next, we performed 25 trials using the conventional method, in which skilled nurses manually connect the needle. In both methods, we thoroughly counted the air bubbles with our naked eyes. We predicted that the capped needle would leave few bubbles in the circuit. In order to evaluate fewer bubbles, we conducted an additional experiment using a microparticle counter to measure the size and number of the bubbles. RESULTS: We thoroughly searched for air bubbles during each of the ten tests but could not find any bubbles visible to the naked eye. In the conventional method, bubbles were visible in 29 out of 50 cases. The bubble count was significantly lower in the capped-needle method than in the conventional method (p < 0.0001, Pearson's χ2 test). In the additional experiments using the microparticle counter, the average remaining air volume in the extracorporeal circuit was 0.0999 ± 0.2438 nL when the priming was performed using the novel capped needles. CONCLUSION: The novel capped needle eliminated all visible bubbles efficiently and effectively; therefore, it could be a valuable device for hemodialysis treatment. The reduction of air from the dialysis circuit may improve patient prognosis.

DOI： 10.1159/000524357

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BACKGROUND: Dual antiplatelet therapy (DAPT) with aspirin plus P2Y12 inhibitor is used as a standard therapy for patients with acute myocardial infarction (AMI) treated with drug-eluting stents (DESs). In Japan, clopidogrel was the major P2Y12 inhibitor used for a decade until the new P2Y12 inhibitor, prasugrel, was introduced. Based on clinical studies considering Japanese features, the set dose for prasugrel was reduced to 20 mg as a loading dose (LD) and 3.75 mg as a maintenance dose (MD); these values are 60 and 10 mg, respectively, globally. Despite this dose discrepancy, little real-world clinical data regarding its efficacy and safety exist. METHODS: From the K-ACTIVE registry, based on the DAPT regimen, patients were divided into a prasugrel group and a clopidogrel group. The ischemic event was a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The bleeding event was type 3 or 5 bleeding based on the Bleeding Academic Research Consortium (BARC) criteria. RESULTS: Substantially more patients were prescribed prasugrel (n = 2786) than clopidogrel (n = 890). Clopidogrel tended to be selected over prasugrel in older patients with numerous comorbidities. Before adjustments were made, the cumulative incidence of ischemic events at 1 year was significantly greater in the clopidogrel group than in the prasugrel group (p = 0.007), while the cumulative incidence of bleeding events at 1 year was comparable between the groups (p = 0.131). After adjustments were made for the age, sex, body weight, creatine level, type of AMI, history of MI, approach site, oral anticoagulation therapy, presence of multivessel disease, Killip classification, and presence of intra-aortic balloon pumping, both ischemic and bleeding events became comparable between the groups. CONCLUSION: A Japanese dose of prasugrel was commonly used in AMI patients in the real-world database. Both the prasugrel and clopidogrel groups showed comparable rates of 1 year ischemic and bleeding events.

DOI： 10.3390/jcm11072016

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DOI： 10.1016/j.chest.2021.05.077

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A recent study has shown that the heterogeneity of native T1 mapping may be a new prognostic factor for patients with non-ischemic dilated cardiomyopathy (NIDCM). This study aimed to investigate the predictive value of native T1 heterogeneity of the left ventricular (LV) myocardium, as assessed by pixel-wise histogram analysis, for predicting left ventricular reverse remodeling (LVRR) by medical therapy in patients with NIDCM. A total of one hundred and thirteen NIDCM patients (mean age: 63 ± 12 years; 91 males and 22 females; mean LV ejection fraction (EF): 37 ± 10%) were retrospectively analyzed. T1 mapping images were acquired using a modified look-locker inversion recovery (MOLLI) sequence. We performed histogram analysis of native T1 mapping of LV myocardium, mean (T1-mean) and standard deviation (T1-STD) of native T1 time from each pixel were calculated. Extracellular volume fraction (ECV) was also evaluated. LVRR was defined as LVEF increased ≥ 10% points and decrease in LV end-diastolic volume ≥ 10% at 12 months from initiation of medical therapy. Cutoff value of T1-mean and T1-STD was set as median value of each parameter. Sixty (53%) NIDCM patients reached LVRR. Area under the receiver-operating characteristics curve for predicting LVRR was 0.763 (95% confidence interval (CI) 0.679-0.847) for %LGE, 0.757 (95% CI 0.663-0.850) for T1-mean, 0.724 (95% CI 0.625-0.823) for T1-STD, 0.800 (95% CI 0.717-0.882) for ECV, respectively. Proportion of LVRR was significantly lower in NIDCM patients with high T1-mean and high T1-STD (12%) compared to NIDCM with high T1-mean and low T1-STD (65%) (p < 0.001). Adding T1-STD to T1-mean improved AUC from 0.757 to 0.806, comparable to AUC of ECV. Combination of T1-mean and T1-STD, a parameter of heterogeneity of native T1 of the LV myocardium, may be a useful for prediction of LVRR by medical therapy without use of gadolinium contrast for patients with NIDCM.

DOI： 10.1007/s00380-022-02057-4

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In this systematic review and meta-analysis, we sought to evaluate the prevalence of cardiac involvement in patients with COVID-19 using cardiac magnetic resonance imaging. A literature review was performed to investigate the left ventricular (LV) and right ventricular (RV) ejection fraction (EF), the prevalence of LV late gadolinium enhancement (LGE), pericardial enhancement, abnormality on T1 mapping, and T2 mapping/T2-weighted imaging (T2WI), and myocarditis (defined by modified Lake Louis criteria). Pooled mean differences (MD) between COVID-19 patients and controls for LVEF and RVEF were estimated using random-effects models. We included data from 10.462 patients with COVID-19, comprising 1.010 non-athletes and 9.452 athletes from 29 eligible studies. The meta-analysis showed a significant difference between COVID-19 patients and controls in terms of LVEF [MD = - 2.84, 95% confidence interval (CI) - 5.11 to - 0.56, p < 0.001] and RVEF (MD = - 2.69%, 95% CI - 4.41 to - 1.27, p < 0.001). However, in athletes, no significant difference was identified in LVEF (MD = - 0.74%, 95% CI - 2.41 to - 0.93, p = 0.39) or RVEF (MD = - 1.88%, 95% CI - 5.21 to 1.46, p = 0.27). In non-athletes, the prevalence of LV LGE abnormalities, pericardial enhancement, T1 mapping, T2 mapping/T2WI, myocarditis were 27.5% (95%CI 17.4-37.6%), 11.9% (95%CI 4.1-19.6%), 39.5% (95%CI 16.2-62.8%), 38.1% (95%CI 19.0-57.1%) and 17.6% (95%CI 6.3-28.9%), respectively. In athletes, these values were 10.8% (95%CI 2.3-19.4%), 35.4% (95%CI - 3.2 to 73.9%), 5.7% (95%CI - 2.9 to 14.2%), 1.9% (95%CI 1.1-2.7%), 0.9% (0.3-1.6%), respectively. Both LVEF and RVEF were significantly impaired in COVID-19 patients compared to controls, but not in athletes. In addition, the prevalence of myocardial involvement is not negligible in patients with COVID-19.

DOI： 10.1007/s00380-022-02055-6

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AIMS: This study aimed to clarify the differences in how sodium glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP1Ra) influence kidney function in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: We retrospectively built two databases of patients with T2DM who visited the clinics of members of Kanagawa Physicians Association. We defined the renal composite outcome as either progression of albuminuria status and/or > 15% deterioration in estimated glomerular filtration rate (eGFR) per year. We used propensity score matching to compare patient outcomes after SGLT2i and GLP1Ra treatments. RESULTS: The incidence of renal composite outcomes was significantly lower in SGLT2i-treated patients than in GLP1Ra-treated patients (n = 15[11%] and n = 27[20%], respectively, P = 0.001). Annual eGFR changes (mL/min/1.73 m2/year) between the two groups differed significantly (-1.8 [95 %CI, -2.7, -0.9] in SGLT2i-treated patients and - 3.4 [95 %CI, -4.6, -2.2] in GLP1Ra-treated patients, P = 0.0049). The urine albumin-to-creatinine ratio changed owing to a significant interaction between the presence or absence of a decrease in systolic blood pressure and the difference in treatments (P < 0.04). CONCLUSION: Renal composite outcome incidence was lower in SGLT2i-treated patients than in GLP1Ra-treated patients.

DOI： 10.1016/j.diabres.2022.109231

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：English   Publisher：(一社)日本循環器学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Pulmonary hypertension (PH) is a severe and progressive disease that causes elevated right ventricular systolic pressure, right ventricular hypertrophy and ultimately right heart failure. However, the underlying pathophysiologic mechanisms are poorly understood. We previously showed that 3,4-l-dihydroxylphenyalanine (DOPA) sensitizes vasomotor response to sympathetic tone via coupling between the adrenergic receptor alpha1 (ADRA1) and a G protein-coupled receptor 143 (GPR143), a DOPA receptor. We investigated whether DOPA similarly enhances ADRA1-mediated contraction in pulmonary arteries isolated from rats, and whether GPR143 is involved in the PH pathogenesis. Pretreating the isolated pulmonary arteries with DOPA 1 μM enhanced vasoconstriction in response to phenylephrine, an ADRA1 agonist, but not to U-46619, a thromboxane A2 agonist or endothelin-1. We generated Gpr143 gene-deficient (Gpr143-/y) rats, and confirmed that DOPA did not augment phenylephrine-induced contractile response in Gpr143-/y rat pulmonary arteries. We utilized a rat model of monocrotaline (MCT)-induced PH. In the MCT model, the right ventricular systolic pressure was attenuated in the Gpr143-/y rats than in WT rats. Phenylephrine-induced cell migration and proliferation were also suppressed in Gpr143-/y pulmonary artery smooth muscle cells than in WT cells. Our result suggests that GPR143 is involved in the PH pathogenesis in the rat models of PH.

DOI： 10.1016/j.jphs.2021.11.008

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Language：Japanese   Publisher：(一社)日本内科学会  

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A 56-year-old man was admitted with a diagnosis of non-ST-segment elevation myocardial infarction, after surgery for total arch replacement, aortic root replacement with a mechanical aortic valve, and coronary artery reconstruction by the Piehler method for acute aortic dissection. Coronary angiography (CAG) revealed a 99% stenosis of the anastomosis site between the J Graft (Japan Lifeline, Tokyo, Japan) and the saphenous vein graft (SVG), which was distally sutured to his right coronary artery (posterior descending artery). After percutaneous coronary intervention (PCI) with a drug-eluting stent to the anastomosis site, repeated in-stent restenosis unfortunately occurred. Despite repeated PCIs, he was again admitted due to exertional angina pectoris, with proven inferior myocardial ischemia by stress myocardial perfusion imaging. We therefore decided to use a coronary covered stent for the anastomosis site to seal neointimal proliferation. GRAFTMASTER 2.8/19 mm (Abbott, CA, USA) was implanted in the anastomosis site, and a follow-up CAG one-year later revealed that the covered stent was clearly opened. To the best of our knowledge, this is the first paper to demonstrate the usefulness of a covered stent for repeated restenosis of the anastomosis site between SVG and graft prostheses. <Learning objective: A coronary covered stent is a stent with a membrane designed to seal the rupture site in cases with a coronary rupture. However, coronary covered stent implantation is an optional method in cases with repeated restenosis of the anastomosis site between the saphenous vein graft and graft prosthesis.>.

DOI： 10.1016/j.jccase.2021.07.007

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publisher：神奈川腎炎研究会  

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Balloon aortic valvuloplasty (BAV) was developed as a technique to treat aortic stenosis (AS) and is associated with significant improvements in aortic valve area and trans-aortic valve gradient in the early and immediate periods after the procedure. BAV is commonly performed using a trans-femoral retrograde approach; however, trans-femoral access is associated with frequent access-site bleeding. Among 146 patients with symptomatic severe AS who were treated with BAV in our institution, 123 patients received BAV treatment via a trans-radial approach using a 7-Fr Glidesheath. The balloon size was 16-20 mm for all patients. Echocardiograms were obtained before and after BAV. Patients who received BAV alone (n = 119) were followed up for 3 months, and major adverse events (stroke, re-hospitalization for heart failure, and death) and procedural complications were recorded. At post-procedural echocardiography, the mean trans-valvular gradient (49.7 ± 21.5-42.5 ± 17.6 mmHg; p < 0.0001) was reduced significantly. All patients in this study did not die or require valve surgery within the first 7 days after BAV. Successful BAV was obtained in 45.6% of the patients. No patients had severe aortic insufficiency or BAV access-site bleeding. Three patients died suddenly and 4 patients were readmitted for heart failure. Trans-radial BAV is safe and may be useful as a bridging therapy for trans-catheter aortic valve replacement or surgical aortic valve replacement.

DOI： 10.1007/s12928-021-00825-z

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Pathological activation of kidney angiotensin II (Ang II) type 1 receptor (AT1R) signaling stimulates tubular sodium transporters, including epithelial sodium channels, to increase sodium reabsorption and blood pressure. During a search for a means to functionally and selectively modulate AT1R signaling, a molecule directly interacting with the carboxyl-terminal cytoplasmic domain of AT1R was identified and named AT1R-associated protein (ATRAP/Agtrap). We showed that ATRAP promotes constitutive AT1R internalization to inhibit pathological AT1R activation in response to certain stimuli. In the kidney, ATRAP is abundantly distributed in epithelial cells along the proximal and distal tubules. Results from genetically engineered mice with modified ATRAP expression show that ATRAP plays a key role in the regulation of renal sodium handling and the modulation of blood pressure in response to pathological stimuli and further suggest that the function of kidney tubule ATRAP may be different between distal tubules and proximal tubules, implying that ATRAP is a target of interest in hypertension.

DOI： 10.1038/s41440-021-00776-1

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DOI： 10.1038/s41440-021-00781-4

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BACKGROUND: Landiolol enables us to treat the patients with rapid atrial fibrillation (AF) with acute decompensated heart failure (ADHF) efficiently. We sought to determine the role of echocardiography in predicting the prognosis. METHODS: Among 314 patients, a total 115 ADHF patients with reduced ejection fraction and rapid AF were enrolled. They received landiolol treatment to decrease the heart rate (HR) to <110 bpm and change HR (ΔHR) of >20% within 24 h. The dose of landiolol was increased every 2 h; then, we performed echocardiography repeatedly, at baseline, 2 h, and 24h. We followed the patients after discharge for 180 days, and checked cardiac death and HF hospitalization as major adverse cardiac events (MACE). RESULTS: During initial hospitalization, 5 patients (4%) died. During 180 days after discharge, 19 (16%) out of 115 patients experienced MACE (2 cardiac death, 17 HF rehospitalization, 5 in-hospital death). Multivariate analysis showed that the change in left ventricular outflow tract-velocity time integral (LVOT-VTI) at 2 h was the most significant predictor for MACE (hazard ratio =1.21, 95% confidence interval: 1.10-1.83, p=0.0001). Kaplan-Meier curves demonstrated the patients with deteriorated LVOT-VTI at minimum dose landiolol suggested the high-risk patients for MACE (χ2=30.9, p<0.0001). CONCLUSIONS: During landiolol treatment, the patients with deteriorated LVOT-VTI predicted the poor prognosis. We may detect the high-risk patients by two-point echocardiography. UMIN000020084. Registered 1 November 2013 - prospective study https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&language=J&recptno=R000023203.

DOI： 10.1016/j.jjcc.2021.09.008

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Background: Tolvaptan is the gold standard treatment for autosomal dominant polycystic kidney disease (ADPKD), while several other drugs have the potential to inhibit the progression of ADPKD. However, individual clinical trials may not show sufficient differences in clinical efficacy due to small sample sizes. Furthermore, the differences in therapeutic efficacy among drugs are unclear. Herein, we investigated the effect of the ADPKD treatments. Methods: We systematically searched PubMed, Medline, EMBASE, and the Cochrane Library through January 2022 to identify randomized controlled trials in ADPKD patients that compared the effects of treatments with placebo or conventional therapy. A network meta-analysis was performed to compare the treatments indirectly. The primary outcomes were changes in kidney function and the rate of total kidney volume (TKV) growth. Results: Sixteen studies were selected with a total of 4,391 patients. Tolvaptan significantly preserved kidney function and inhibited TKV growth compared to the placebo {standardized mean difference (SMD) [95% confidence interval (CI)]: 0.24 (0.16; 0.31) and MD: -2.70 (-3.10; -2.30), respectively}. Tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors inhibited TKV growth compared to the placebo; somatostatin analogs significantly inhibited TKV growth compared to the placebo and tolvaptan [MD: -5.69 (-7.34; -4.03) and MD: -2.99 (-4.69; -1.29), respectively]. Metformin tended to preserve renal function, although it was not significant [SMD: 0.28 (-0.05; 0.61), p = 0.09]. Conclusion: The therapeutic effect of tolvaptan was reasonable as the gold standard for ADPKD treatment, while somatostatin analogs also showed notable efficacy in inhibiting TKV growth. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022300814.

DOI： 10.3389/fphar.2022.885457

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Language：Japanese   Publisher：Japanese Pharmacological Society  

We previously demonstrated that L-DOPA modulated the vascular α1-adrenergic receptor through GPR143, a G-protein coupled receptor, and sensitized vasomotor tone. In this study, we examined a possible role of GPR143 in the pathogeneisis of pulmonary hypertension (PH). In isolated pulmonary arteries, L-DOPA (1 μM) augmented contractile response to phenylephrine, an α1 adrenergic receptor agonist. We generated GPR143 gene-deficient (<i>Gpr143</i>^<i>-/y</i>) rats and comparatively studied the effect of L-DOPA. L-DOPA did not modify phenylephrine-induced response in the pulmonary arteries of <i>Gpr143</i>^<i>-/y</i> rats, thereby indicating that the action of L-DOPA was mediated by GPR143. We next established monocrotaline (MCT, 60 mg/kg) -induced PH model in wild type (WT) and <i>Gpr143</i>^<i>-/y</i> rats. One month after injection subcutaneously with MCT , the right ventricular systolic pressure (RVSP) was attenuated in <i>Gpr143</i>^<i>-/y</i> rats as compared to the WT rats (49.7 +/- 1.1 mmHg and 41.4 +/- 1.4 mmHg in WT and <i>Gpr143</i>^<i>-/y</i>, p&lt;0.05, N=5). Coordinately, the right ventricle to body weight (RV/BW) (5.4 +/- 0.2 × 10^-4 and 4.7 +/- 0.1 × 10^-4 in WT and <i>Gpr143</i>^<i>-/y</i>, p&lt;0.01, N=12) was also reduced in <i>Gpr143</i>^<i>-/y</i> rats compared to the WT rats. Furthermore, in primary cultures of pulmonary artery smooth muscle cells (PASMCs), the proliferative and migratory capacity of <i>Gpr143</i>^<i>-/y</i> PASMCs after phenylephrine treatment was reduced compared to <i>Gpr143</i>-WT PASMCs. We here provide evidence that GPR143 may be involved in MCT-induced PH in rats by affecting the proliferative and migratory capacity of PASMCs.

DOI： 10.1254/jpssuppl.95.0_1-yia-06

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The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na+ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

DOI： 10.3390/ijms23010302

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To prevent further spread of coronavirus disease 2019 (COVID-19), the Japanese government announced a state of emergency, resulting in major stress for the population. The aim of this study was to investigate a possible association between changes in daily stress and blood pressure (BP) in Japanese patients. We retrospectively investigated 748 patients with chronic disease who were treated by the Sagamihara Physicians Association to determine changes in stress during the COVID-19 state of emergency from 7 April to 31 May 2020. During the state of emergency, office BP significantly increased from 136.5 ± 17.5/78.2 ± 12.0 to 138.6 ± 18.6/79.0 ± 12.2 (p < 0.001 and p = 0.03, respectively). In contrast, home BP significantly decreased from 128.2 ± 10.3/75.8 ± 8.8 to 126.9 ± 10.2/75.2 ± 9.0 (p < 0.001 and p = 0.01, respectively), and the ratio of white coat hypertension was significantly increased (p < 0.001). Fifty-eight percent of patients worried about adverse effects of hypertension as a condition contributing to the severity and poor prognosis of COVID-19; decreased amounts of exercise and worsened diet compositions were observed in 39% and 17% of patients, respectively. In conclusion, a significant increase in office BP with the white coat phenomenon was observed during the state of emergency, as well as an increase in related stress. To prevent cardiovascular events, general practitioners should pay more attention to BP management during stressful global events, including the COVID-19 pandemic.

DOI： 10.1038/s41440-021-00832-w

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BACKGROUND: Two-dimensional (2D) and three-dimensional (3D) speckle tracking echocardiography (STE) after ST-elevation acute myocardial infarction (STEMI) can predict the prognosis. This study investigated the clinical significance of a serial 3D-STE can predict the prognosis after onset of STEMI.Methods and Results:This study enrolled 272 patients (mean age, 65 years) with first-time STEMI treated with reperfusion therapy. At 24 h after admission, standard 2D echocardiography and 3D full-volume imaging were performed, and 2D-STE and 3D-STE were calculated. Within 1 year, 19 patients who experienced major adverse cardiac events (MACE; cardiac death, heart failure requiring hospitalization) were excluded. Among the 253 patients, 248 were examined with follow-up echocardiography. The patients were followed up for a median of 108 months (interquartile range: 96-129 months). The primary endpoint was the occurrence of a MACE; 45 patients experienced MACEs. Receiver operating characteristic curves and Cox hazard multivariate analysis showed that the 2D-global longitudinal strain (GLS) and 3D-GLS at 1-year indices were significant predictors of MACE. The Kaplan-Meier curve demonstrated that a 3D-GLS of >-13.1 was an independent predictor for MACE (log-rank χ2=165.5, P<0.0001). The deterioration of 3D-GLS at 1 year was a significant prognosticator (log-rank χ2=36.7, P<0.0001). CONCLUSIONS: The deterioration of 3D-GLS measured by STE at 1 year after the onset of STEMI is the strongest predictor of long-term prognosis.

DOI： 10.1253/circj.CJ-21-0815

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Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1β, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

DOI： 10.1038/s41598-021-02864-1

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INTRODUCTION: The erythropoietin resistance index (ERI) is an indicator of erythropoiesis-stimulating agent (ESA) responsiveness and is typically calculated using Hb. However, Hb does not directly reflect ESA-induced erythropoiesis because of its long-term nature. We thus designed a novel ERI calculated with reticulocyte Hb (RetHb), a real-time index, and investigated its association with mortality in HD patients. METHODS: We calculated the ERI using the change in RetHb before and after ESA administration (ERIΔRetHb ) and retrospectively analyzed its association with 3-year all-cause mortality using Kaplan-Meier survival curves and Cox regression analyses. RESULTS: A total of 102 patients were included. Patients with the highest ERIΔRetHb had the worst prognosis according to the Kaplan-Meier survival curves (Log-rank p = 0.02). Multivariate Cox regression analysis showed that the ERIΔRetHb was significantly and independently associated with all-cause mortality (hazard ratio: 9.82, 95% CI [1.50, 64.41], p = 0.02). CONCLUSION: The ERIΔRetHb was significantly and independently associated with all-cause mortality in HD patients.

DOI： 10.1111/1744-9987.13772

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Language：Japanese   Publisher：(一社)日本痛風・尿酸核酸学会  

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Background Recent data suggest that the angiotensin receptor neprilysin inhibitor modulates plasma levels of natriuretic peptides and attenuates the risk of hyperkalemia in patients with heart failure (HF). However, the impact of natriuretic peptides on serum electrolyte abnormalities, especially abnormalities in sodium and potassium levels in patients with HF remains unclear. Methods We performed a post-hoc analysis of a multicenter prospective cohort study in 162 patients with acute HF (74.2 ± 13.3 years, 64.2% male, left ventricular ejection fraction 44 ± 15%) treated with intravenous carperitide, an exogenous atrial natriuretic peptide. Results The dose of carperitide was correlated with urine volume (σ = 0.205, p = 0.009), suggesting a significant diuretic effect. During the initial 48 h, serum sodium level remained unchanged both in 53 patients with carperitide alone (from 140 ± 4 to 140 ± 3 mEq/L, p = 0.653) and 109 patients treated with a combination of carperitide and furosemide (141 ± 4 to 141 ± 4 mEq/L, p = 0.644). On the contrary, serum potassium level was decreased both in patients with carperitide alone (from 4.32 ± 0.70 to 4.08 ± 0.47 mEq/L, p = 0.004) and patients treated with a combination of carperitide and furosemide (4.17 ± 0.55 to 3.98 ± 0.47, p < 0.001), with a significant association between urine volume and change in potassium level in patients treated with carperitide alone (σ = -0.313, p = 0.023). The incidence of hypokalemia at 24 h was higher in patients treated with 20 mg furosemide or more (12.5% vs. 2.8%, p = 0.039). Conclusions Serum potassium level decreased after HF treatment with exogenous atrial natriuretic peptide, with a significant correlation to urine volume. The risk of hypokalemia was low, unless treated with additional furosemide.

DOI： 10.1016/j.jjcc.2021.08.002

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BACKGROUND: Low physical performance may contribute to reduced exercise capacity in older patients with heart failure (HF). We sought to identify the determinants of exercise capacity out of a plethora of background factors, including measures of physical performance. METHODS: We performed a post-hoc analysis of a cohort study that included 1205 consecutive older (age ≥ 65 years) hospitalized patients (the median age, 80 years; 57.4% males). RESULTS: Low physical performance, defined as ≤1.0 m/s for gait speed, ≥12 s for the 5-time chair stand test, or ≤ 9 points for the Short Physical Performance Battery in both sexes, was seen in 83.9% of the cohort. Multivariate regression analysis revealed that each parameter of physical performance (i.e., gait speed, chair stand test, and balance test) was identified as an independent determinant of lower exercise capacity assessed using the 6-min walking distance. In a logistic regression model, low physical performance predicted short (<300 m) 6-min walking distance (adjusted odds ratio 10.28, 95% CI 6.01-17.60, p < 0.001). No interaction was detected between patients with preserved and reduced ejection fraction. CONCLUSIONS: Low physical performance was prevalent and independently associated with exercise capacity in older patients with HF, irrespective of preserved or reduced ejection fraction.

DOI： 10.1016/j.exger.2021.111626

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BACKGROUND: In Japan, six types of sodium-glucose cotransporter inhibitors (SGLT2Is) are currently in use. Here, we evaluated differences in renal composite outcomes between SGLT2Is with or without evidence of cardio vascular outcome trials (CVOTs). METHODS: We retrospectively surveyed 536 Japanese patients with type 2 diabetes mellitus with chronic kidney disease who received SGLT2Is for more than 1 year. Patients were classified as having received empagliflozin, canagliflozin, or dapagliflozin (n = 270, Evidence (+) group) or as having received ipragliflozin, tofogliflozin, or luseogliflozin (n = 266, Evidence (-) group). The propensity score matching method was performed. RESULT: On matched cohort model including 205 cases in each group, there were no significant differences in the incidence of renal composite outcomes (n = 28 [14%] in the Evidence (+) group, n = 21 [10%] in the Evidence (-) group for the matched model; p = 0.29) between groups. Cox hazard analyses in the matched cohort model showed that the risk ratio for renal composite outcomes in the Evidence (-) group was 0.73 (95% confidence interval: 0.40-1.32), which was greater than the noninferiority margin of 1.22. CONCLUSION: Three SGLT2Is with no CVOT's evidence did not show noninferiority compared with other SGLT2Is with evidences.

DOI： 10.1016/j.pcd.2021.08.012

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The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

DOI： 10.3390/ijms222212432

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To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

DOI： 10.3390/mps4040083

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AIMS: It remains unclear which sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are most effective for preventing cardiovascular and renal events in type 2 diabetes mellitus (T2DM) patients, depending on the presence of albuminuria. We conducted a network meta-analysis to compare the efficacy of these two drug classes in T2DM patients with/without albuminuria. METHODS: We searched the Medline, EMBASE, Cochrane Library databases, and gray literature up to April 20, 2021. We included randomized controlled trials that reported the risk of major adverse cardiovascular events (MACE) and composite of renal outcomes in T2DM. RESULTS: A total of nine studies (81,206 patients) were included. In patients with/without albuminuria, SGLT-2 inhibitors did not significantly reduce the risk of MACE compared with GLP-1 RAs (risk ratio [RR] [95% confidence interval]; 0.96 [0.82-1.12] and 0.94 [0.81-1.10], respectively). In contrast, compared with GLP-1 RAs, SGLT-2 inhibitors were associated with significantly lower renal risk in both patients with/without albuminuria (RR [95% CI]; 0.75 [0.63-0.89] and 0.59 [0.44-0.79], respectively). CONCLUSIONS: SGLT-2 inhibitors may be superior to GLP-1 RAs for renal outcomes in T2DM patients with/without albuminuria, although there was no difference in the risk of MACE.

DOI： 10.1016/j.diabres.2021.109146

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BACKGROUND: We previously showed Lipin1 (LPIN1) to be a candidate gene for essential hypertension by genome-wide association studies. LPIN1 encodes the Lipin 1 protein, which contributes to the maintenance of lipid metabolism and glucose homeostasis. However, little is known about the association between LPIN1 and blood pressure (BP). METHODS: We evaluated the BP of LPIN1-deficient [fatty liver dystrophy (fld)] mice and explored related mechanisms. RESULTS: Fld mice have very low expression of LPIN1 and exhibit fatty liver, hypertriglyceridemia, insulin resistance and peripheral neuropathy. Fld mice had significantly elevated SBP and heart rate (HR) throughout the day as measured by a radiotelemetric method. Diurnal variation of SBP and HR was also absent in fld mice. Furthermore, urinary excretion of adrenaline and noradrenaline by fld mice was significantly higher compared with that of control mice. The BP response of fld mice to clonidine (a centrally acting α2-adrenergic receptor agonist) was greater than that of control mice. However, levels of Angiotensinogen and Renin 1 mRNA and urinary nitric oxide excretion were comparable between the two groups. The decrease in SBP at 8 weeks after fat grafting surgery was significantly greater in the transplant group compared with the sham operated group. CONCLUSION: The elevated BP in fld mice may result from activation of the sympathetic nervous system through decreased levels of adipose cytokines. These results indicate that LPIN1 plays a crucial role in blood pressure regulation and that LPIN1 is a new target gene for essential hypertension.

DOI： 10.1097/HJH.0000000000003046

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Whether free fatty acids (FFAs), which are generators of reactive oxygen species and substrates of cytotoxic lipid peroxidation products in proximal tubules of the kidney, can be a predictor of worsening renal function (WRF) is not fully elucidated. A total of 110 patients with ST-segment elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention within 24 h after symptom onset were included. The exclusion criteria were out-of-hospital cardiac arrest, vasospastic angina, hemodialysis, and/or lack of data. FFAs and serum cystatin C were measured on admission, and urinary liver-type fatty acid-binding protein (L-FABP) was measured 3 h after admission. WRF, defined as an increase in serum creatinine by ≥ 0.3 mg/dL for 2-year follow-up, was observed in 16 patients (15%). A multivariate logistic regression analysis (a stepwise algorithm) revealed that the FFA level was an independent predictor of WRF (P = 0.024). The FFA level was associated with WRF adjusted after serum cystatin C (odds ratio [OR]: 1.378 per 1 mEq/L, P = 0.017), L-FABP (OR: 1.370 per 1 mEq/L, P = 0.016), or the Mehran contrast-induced nephropathy (CIN) risk score (OR: 1.362 per 1 mEq/L, P = 0.021). The FFA level was inversely associated with the change in estimated glomerular filtration rate level for 2 years (R2 = 0.051, P = 0.018). The FFA level on admission was associated with the mid-term WRF in patients with STEMI.

DOI： 10.1007/s00380-021-01982-0

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OBJECTIVE: Primary aldosteronism has two main clinically and biologically distinct subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). We aimed to evaluate the changes of each subtype's clinical characteristics over a 13-year period. METHODS: This retrospective study involved time-trend analyses to identify changes in the clinical features of APA and BAH at diagnosis (2006-2018). A nationwide database from 41 Japanese referral centers was searched, which identified 2804 primary aldosteronism patients with complete baseline information and adrenal venous sampling (AVS) data. RESULTS: The proportion of patients with APA decreased from 51% in 2006-2009 to 22% in 2016-2018. Among the 1634 patients with BAH, trend analyses revealed decreases in hypertension duration (median 7--3 years; P < 0.01) and hypokalemia prevalence (18--11%; P < 0.01). However, among the 952 patients with APA, there were no significant changes in hypertension duration (median 8 years) and hypokalemia prevalence (overall 70%). Furthermore, the APA group had a trend towards increased use of multiple hypertensive drugs at diagnosis (30--43%; P < 0.01). When subtypes were reclassified according to the precosyntropin stimulation AVS data, APA patients tended to be diagnosed earlier and at milder forms, consistent with the trend in overall primary aldosteronism patients. CONCLUSION: During 2006-2018, we identified marked subtype-specific trends in the clinical findings at the diagnosis of primary aldosteronism. Our results suggested that the emphasis on the implementing cosyntropin stimulation during AVS might lead to under-identification of APA, especially in patients with mild or early cases.

DOI： 10.1097/HJH.0000000000002924

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OBJECTIVE: Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS: Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS: At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m2, and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m2 per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P heterogeneity ≥ 0.35). CONCLUSIONS: The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.

DOI： 10.2337/dc21-1081

PubMed

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Language：English   Publishing type：Research paper (scientific journal)  

Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.

DOI： 10.1007/s13730-021-00605-x

PubMed

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