Hiromi Rakugi’s research while affiliated with Osaka Rosai Hospital and other places

The relationship between frailty and blood pressure (BP) is inconsistent, and limited research has compared BP by frailty status using long-term home BP measurements. We aimed to identify office and home BP and determine differences according to frailty status, stratified by taking antihypertensives in community-dwelling older adults. This cross-sectional study was part of the ongoing non-randomized intervention NOSE study. Participants were aged ≥ 64 years. Frailty was categorized robust, pre-frailty, or frailty using the revised Japanese version of the Cardiovascular Health Study criteria. Office BP was measured in survey settings, and each participant was instructed to take home BP. We used the average home BP for 4 weeks post-survey. An analysis of covariance analyzed the relationship between frailty and office and home BP, and their differences stratified by antihypertensive use. We included 418 older participants (mean age: 72.8 years); 39.5% were male, 40.4% were taking antihypertensives, and 6.7% had frailty. Individuals with frailty taking antihypertensives had higher home morning systolic BP (SBP) than those with robust (134.2 vs. 145.7 mmHg, P = 0.018) and pre-frailty (135.6 vs. 145.7 mmHg, P = 0.024). The difference between office and morning home SBP in treated participants was 7.1 mmHg (robust), 4.7 mmHg (pre-frailty), and −5.1 mmHg (frailty), showing significant differences (robust vs. frailty: P = 0.005, pre-frailty vs. frailty: P = 0.016). Home morning SBP was higher in individuals with frailty taking antihypertensives compared to those without frailty, and it may be higher than office BP. Individuals with frailty should measure home BP for good BP control.

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.

The renin-angiotensin system (RAS) is a classically known circulatory regulatory system. In addition to the previously known multi-organ circulatory form of the RAS, the existence of tissue RASs in individual organs has been well established. Skeletal muscle has also been identified as an organ with a distinct RAS. In recent years, the effects of RAS activation on skeletal muscle have been elucidated from several perspectives: differences in motor function due to genetic polymorphisms of RAS components, skeletal muscle dysfunction under conditions of excessive RAS activation such as heart failure, and the effects of the use of RAS inhibitors on muscle strength. In addition, the concept of the RAS itself has recently been expanded with the discovery of a ‘protective arm’ of the RAS formed by factors such as angiotensin-converting enzyme 2 and angiotensin 1-7. This has led to a new understanding of the physiological function of the RAS in skeletal muscle. This review summarizes the diverse physiological functions of the RAS in skeletal muscle and considers the potential of future therapeutic strategies targeting the RAS to overcome problems such as sarcopenia and muscle weakness associated with chronic disease.

Sacubitril/valsartan, an angiotensin receptor‐neprilysin inhibitor, has demonstrated a superior blood pressure‐lowering effect compared with renin‐angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well‐established class of antihypertensive drugs. In this open‐label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥ 150 to < 180 mmHg), aged 18–79, were randomly assigned to receive either once‐daily sacubitril/valsartan 200 mg or once‐daily amlodipine 5 mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24‐h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24‐h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between‐treatment difference −0.62 mmHg [95% confidential interval: −3.23 to 1.98; p = 0.003 for noninferiority; independent t‐test with noninferiority margin 3.0 mmHg]), with no significant difference observed (p = 0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure‐lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

BACKGROUND Myofibroblasts are primary cells involved in chronic response-induced cardiac fibrosis. Fibroblast activation protein (FAP) is a relatively specific marker of activated myofibroblasts and a potential target molecule. This study aimed to clarify whether a vaccine targeting FAP could eliminate myofibroblasts in chronic cardiac stress model mice and reduce cardiac fibrosis. METHODS We coadministered a FAP peptide vaccine with a CpG K3 oligonucleotide adjuvant to male C57/BL6J mice and confirmed an elevation in the anti-FAP antibody titer. After continuous angiotensin II and phenylephrine administration for 28 days, we evaluated the degree of cardiac fibrosis and the number of myofibroblasts in cardiac tissues. RESULTS We found that cardiac fibrosis was significantly decreased in the FAP-vaccinated mice compared with the angiotensin II and phenylephrine control mice (3.45±1.11% versus 8.62±4.79%; P =4.59×10 ⁻³ ) and that the accumulation of FAP-positive cells was also significantly decreased, as indicated by FAP immunohistochemical staining (4077±1746 versus 7327±1741 cells/mm ² ; FAP vaccine versus angiotensin II and phenylephrine control; P =6.67×10 ⁻ ³ ). No systemic or organ-specific inflammation due to antibody-dependent cell cytotoxicity induced by the FAP vaccine was observed. Although the transient activation of myofibroblasts has an important role in maintaining the structural robustness in the process of tissue repair, the FAP vaccine showed no adverse effects in myocardial infarction and skin injury models. CONCLUSIONS Our study demonstrates the FAP vaccine can be a therapeutic tool for cardiac fibrosis.

Hypertension increases the risk of cerebrovascular disease and death. In addition to aerobic exercise, which is currently recommended for its antihypertensive effects, recent studies have suggested that dynamic and isometric resistance exercises also have antihypertensive effects. However, the magnitude of the antihypertensive effect of such resistance exercises is not well known. To clarify the differences in these effects, we conducted an umbrella review of a meta-analysis of randomized controlled trials (RCTs). A systematic search was performed on the Ovid MEDLINE and Cochrane Library, covering the period from inception to August 1, 2023. Eligible studies were RCTs comparing the effects of exercise and non-exercise on office, home, or ambulatory blood pressure (BP) in hypertensive patients aged 18 years or older. A random effects model meta-analysis was performed to estimate the effect size across multiple studies. A sub-analysis determined outcomes by the type of exercise (aerobic exercise, dynamic resistance exercise, isometric resistance exercise, and combined exercise). Eighty-four RCTs with 5065 hypertensive patients were included in the study. All exercise significantly reduced systolic BP (SBP) and diastolic BP (DBP) compared to non-exercise (SBP:-7.52 mmHg, 95% confidence interval [CI] -8.77 to -6.27, p < 0.001; DBP: -4.36 mmHg, 95% CI - 5.15 to -3.57, p < 0.001). There were no significant differences in the magnitude of the reduction in BP between the types of exercise (p for interaction = 0.815 for SBP, p = 0.417 for DBP). These data from 84 RCTs showed that exercise intervention significantly reduced BP and that resistance exercise has a similar antihypertensive effect to aerobic exercise in hypertensive patients. This meta-analysis showed that exercise significantly reduced blood pressure in hypertensive patients. There were no significant differences in the magnitude of this reduction in BP between the types of exercise.

Although hypertension is a major cause of cardiovascular disease, the control of blood pressure (BP) is insufficient worldwide. Exercise is an effective treatment for reducing BP, but the differences in the blood pressure lowering effects of exercise according to the underlying pathophysiological condition, the type of exercise, and the geographic region are not fully understood. An umbrella review with a meta-analysis of 435 randomized controlled trials that investigated the BP-lowering effects of exercise was performed using Ovid MEDLINE and the Cochrane Library, covering the period from inception to August 1, 2023. A random effects model meta-analysis was performed to estimate the effect size across multiple studies. Exercise significantly reduced systolic BP in healthy subjects (-3.51 mmHg, 95% confidence interval: -3.90, -3.11; p < 0.001) and in those with lifestyle-related diseases including hypertension (-5.48 mmHg, -6.51, -4.45; p < 0.001), but not in those with cardiovascular diseases (-1.16 mmHg, -4.08, 1.76; p = 0.44). According to the type of exercise, all types significantly reduced systolic BP in healthy subjects and in those with lifestyle-related diseases, but not in those with cardiovascular diseases. According to the region, in Oceania, there were no reductions in systolic BP. In Asia, systolic BP was reduced in patients with cardiovascular diseases. In conclusion, any type of exercise reduced BP in healthy subjects and in those with lifestyle-related diseases, but not in those with cardiovascular diseases, and the region affected the effect of exercise. When using exercise to reduce hypertension, it is important to consider the patient's pathophysiological condition and the region.

Objective: Previous studies suggest older patients with multiple health conditions and medications may experience adverse interactions, leading to negative outcomes. However, there’s limited research on this in older adults receiving home medical care. This study assesses whether polypharmacy is linked to falls or other clinical outcomes. Methods: The study population included 217 participants, aged ≥65 years, receiving home medical care, who consented to participate in the Osaka Home Care Registry (OHCARE) study in Japan. The survey examined the association between polypharmacy and clinical outcomes. We defined “polypharmacy” as six or more medications taken regularly. Results: Of the participants, 135 (62.6%) had polypharmacy and were significantly more likely to have hypertension or diabetes. Common medications included those for hypertension, diabetes, and mental disorders. Participants with polypharmacy experienced significantly more falls. Multivariate analysis showed an association between polypharmacy and falls (odds ratio: 2.81, 95% confidence interval [1.34, 5.92]). Conclusion: Even in older patients receiving home health care, the use of six or more medications poses a risk of falls. Careful observations and life support by medical stuffs are necessary to prevent falls in older patients with polypharmacy receiving home medical care.

Background Preoperative frailty is a risk factor for postoperative complications and poor prognosis in older patients. We aimed to investigate the impact of preoperative exercise and nutritional interventions on the frequency of postoperative complications, physical function, and activities of daily living (ADL) one year postoperatively in frail older patients with gastrointestinal cancer. Methods This single-center, randomized controlled trial included 62 patients aged ≥ 70 years who were scheduled for elective surgery for gastrointestinal cancer with decreased grip strength or walking speed between October 2017 and December 2022. The participants were randomly assigned to the control (n = 33) and intervention (n = 29) groups. Participants in the intervention group performed resistance exercises and consumed amino acid-containing jelly daily at home for 14 days. All participants were followed up for one year. Variables were compared using the two-sided Student's t-test or Fisher's exact test. Statistical significance was set at p < 0.05. Results After exclusion, 45 patients were included in the analysis, with 27 and 18 in the control and intervention groups, respectively. The average age was 80.4 years, and 37.8% of the participants were male. Postoperative complications were observed in 48.1% and 44.4% of the control and intervention groups, respectively (95% confidence interval (CI) 0.57–2.07). Postoperative delirium was observed in 25.9% and 33.3% of the control and intervention groups, respectively (95% CI 0.31–1.94). No significant differences were observed between the two groups in grip strength, walking speed, and skeletal muscle index during follow-up. However, knee extension strength was better maintained in the intervention group at discharge (preoperatively: 100.2 ± 18.3% vs 119.1 ± 68.8%, p = 0.19; discharge: 86.7 ± 22.0% vs 119.3 ± 72.0%, p = 0.044). The proportion of patients with decreased ADL or death was lower in the intervention group than in the control group one year postoperatively (42.3% vs 23.5%; RR 0.56, 95% CI 0.08–1.92). Conclusions A 14-day preoperative exercise and nutritional intervention program did not significantly reduce the frequency of postoperative complications in frail older patients with gastrointestinal cancer. However, it aided in maintaining knee extension strength at discharge. Trial Registration: UMIN (University Hospital Medical Information Network) Clinical Trials Registry (ID: UMIN000024526), registered on 1 December 2016.