Optimal blood pressure in patients with peripheral artery disease following endovascular therapy.

This study examined the associations between blood pressure (BP) and event incidence to define optimal BP after endovascular therapy (EVT) in patients who underwent EVT. BP was monitored every 6 months for 5 years, and the patients were divided into two groups by average BP: ≥ 140/90 mmHg and < 140/90 mmHg. The association of BP with several events was examined. Although no significant differences in total mortality were observed between the groups, restenosis rates were significantly higher among patients who did not achieve target BP (36.2%) than among those who did (18.2%) (p < 0.01). The percentage of patients with glycosylated haemoglobin > 7.0% was significantly higher among those who did not achieve target BP in the restenosis group (42.9%) than in the other group (10.8%) (p < 0.01). In the restenosis group, there was a significantly higher percentage of patients taking metformin (p < 0.01) than in the other group. Metformin seemed to be administered to patients with more severe diabetes mellitus. In conclusion, it is important to manage hypertension and diabetes to prevent restenosis after EVT.

The impact of elevation of serum uric acid level on the natural history of glomerular filtration rate (GFR) and its sex difference.

BACKGROUND: The impact of elevation of the serum uric acid level (SUA) on the natural history of glomerular filtration rate (GFR) remains controversial. METHODS: If elevation of SUA is a result, rather than a cause, of a decline in GFR, the relationship between SUA and GFR should be the same in the same population over years except for shifts by age-dependent reduction of GFR. We tested this hypothesis using data from two cohorts and a group of allopurinol-treated patients. RESULTS: In Cohort 1 consisting of urban residents aged 40.6 ± 9.0 years (n = 3 446), SUA was inversely correlated with estimated GFR (eGFR) in both men and women, and the slope of the SUA-eGFR relationship was steeper in women than in men. The slopes of the regression lines became significantly steeper after a 6-year interval in both sexes, and the change in the slope was larger in women. A similar sex difference in the SUA-eGFR relationship and 6-year change in the slope were observed in Cohort 2 consisting of rural town residents aged 61.7 ± 12.2 years (n = 404). Multiple regression analyses showed that explanatory factors of eGFR after a 6-year interval were age and SUA at baseline in both cohorts, and partial regression coefficients of SUA were more negative in women than in men. The SUA-eGFR relationship in allopurinol-treated patients (n = 346, 63.5 ± 13.3 years old) was similar to that in Cohort 2. CONCLUSIONS: The results indicate that elevation of SUA accelerates the yearly decline in eGFR and that women are more susceptible to urate-induced decline in eGFR.

[Diabetes mellitus].

Recently renin-angiotensin-aldosterone system (RAAS) including angiotensin converting enzyme (ACE) 2-angiotensin (Ang)-(1-7) system may concern both pancreatic insulin secretion and insulin resistance (IR). Actually, Ang II introduces pancreatic beta-cell apoptosis and suppresses insulin signal transduction by modulation of adipokines. Ang II also suppresses GLUT4 expression and AMP kinase activity. All of them introduce new onset diabetes mellitus and various kinds of diabetic complications. RAAS suppression by using not only ACE inhibitor, Ang II receptor blockade (ARB) but also aldosterone receptor blockade improved insulin secretion and IR. Clinically, ACE inhibitor and ARB suppress new onset diabetes mellitus and diabetic complications. In this review we will focus on the recent findings related RAAS and glucose metabolism and diabetic complications with special reference to ACE2-Ang-(1-7) system.

Difference in Prognosis between Continuation and Discontinuation of A 5-Month Cardiac Rehabilitation Program in Outpatients with Heart Failure with Preserved Ejection Fraction.

BACKGROUND: Cardiac rehabilitation (CR) is a requisite component of care for patients with heart failure (HF). We aimed to evaluate the clinical outcomes in outpatients with HF with preserved ejection fraction (HFpEF) compared to those in patients with non-HFpEF who did and did not continue a 5-month CR program. METHODS: 173 outpatients with HF who participated in a 5-month CR program were registered. We divided them into two groups: HFpEF (n = 84, EF 63 ± 7%) and non-HFpEF (n = 89, EF 31 ± 11%). We further divided the patients into those who continued the CR program (continued group) and those who did not (discontinued group) in the HFpEF and non-HFpEF groups. The clinical outcomes at 5 months were compared among the groups. RESULTS: There were no significant differences in patient characteristics at baseline between the continued and discontinued groups in the HFpEF and non-HFpEF groups except for % diabetes mellitus in the non-HFpEF group. The rates of all-cause death and hospital admissions in the continued group in both the HFpEF and non-HFpEF groups were significantly lower than those in the discontinued group. The all-cause death and hospital admissions in each group were independently associated with the continuation of the CR program. CONCLUSIONS: The continuation of a 5-month CR program was associated with the prevention of all-cause death and hospital admissions in both the HFpEF and non-HFpEF groups.

Elevated circulating FABP4 concentration predicts cardiovascular death in a general population: a 12-year prospective study.

Fatty acid-binding protein 4 (FABP4) is secreted from adipose tissue and acts as an adipokine, and an elevated circulating FABP4 level is associated with metabolic disorders and atherosclerosis. However, little is known about the causal link between circulating FABP4 level and mortality in a general population. We investigated the relationship between FABP4 concentration and mortality including cardiovascular death during a 12-year period in subjects of the Tanno-Sobetsu Study, a population-based cohort (n = 721, male/female: 302/419). FABP4 concentration at baseline was significantly higher in female subjects than in male subjects. All-cause death occurred in 123 (male/female: 74/49) subjects, and 34 (male/female: 20/14) and 42 (male/female: 26/16) subjects died of cardiovascular events and cancer, respectively. When divided into 3 groups according to tertiles of FABP4 level at baseline by sex (T1-T3), Kaplan-Meier survival curves showed that there were significant differences in rates of all-cause death and cardiovascular death, but not cancer death, among the groups. Multivariable Cox proportional hazard model analysis with a restricted cubic spline showed that hazard ratio (HR) for cardiovascular death, but not that for all-cause death, significantly increased with a higher FABP4 level at baseline after adjustment of age and sex. The risk of cardiovascular death after adjustment of age, sex, body mass index and levels of brain natriuretic peptide and high-sensitivity C-reactive protein in the 3rd tertile (T3) group (HR: 4.96, 95% confidence interval: 1.20-22.3) was significantly higher than that in the 1st tertile (T1) group as the reference. In conclusion, elevated circulating FABP4 concentration predicts cardiovascular death in a general population.

Potential prescribing omissions may have no influence on cause of death in care-dependent older adults with percutaneous endoscopic gastrostomy tube.

AIM: Studies of medication use in patients with a percutaneous endoscopic gastrostomy (PEG) tube have not been conducted adequately. The aim of this study was to describe medication use of care-dependent older adults with PEG and evaluate whether potential prescribing omissions (PPO) would affect the cause of death or acute illness. METHODS: In a geriatric long-term care hospital, 116 inpatients aged ≥65 years with insertion of a PEG tube because of dysphagia were enrolled and followed for 2 years: 2016-2018. The patients were divided into two groups, i.e., group A (who died between 2016 and 2018) and group B (who continued to be hospitalized in 2018). Clinical data and prescribed medications were recorded. Logistic regression models were conducted to assess the associations between survival and variables: age, gender, serum albumin level, serum creatinine level, body mass index (BMI), number of drugs and PPO. RESULTS: The patients' mean age was 85.3 ± 10.2 years, 57.8% were women and the mean number of drugs was 6.8 ± 3.5. Medications for managing symptoms, such as constipation and gastrointestinal symptoms, were commonly prescribed. The most common PPO medications were antiplatelet agents and anticoagulants. On logistic regression analysis, PPO had no influence on the cause of death or acute illness. Lower age, higher serum albumin level and body mass index were associated with survival in both univariate and multivariate models. CONCLUSIONS: Polypharmacy was prevalent in patients with PEG. Given the finding that PPO had no influence on health outcome, rational deprescribing could be warranted. Geriatr Gerontol Int 2020; 20: 961-966.

Prevalence of chronic kidney disease in the Japanese general population.

BACKGROUND: We previously estimated the prevalence of chronic kidney disease (CKD) stages 3-5 at 19.1 million based on data from the Japanese annual health check program for 2000-2004 using the Modification of Diet in Renal Disease (MDRD) equation multiplied by the coefficient 0.881 for the Japanese population. However, this equation underestimates the GFR, particularly for glomerular filtration rates (GFRs) of over 60 ml/min/1.73 m(2). We did not classify the participants as CKD stages 1 and 2 because we did not obtain proteinuria data for all of the participants. We re-estimated the prevalence of CKD by measuring proteinuria using a dipstick test and by calculating the GFR using a new equation that estimates GFR based on data from the Japanese annual health check program in 2005. METHODS: Data were obtained for 574,024 (male 240,594, female 333,430) participants over 20 years old taken from the general adult population, who were from 11 different prefectures in Japan (Hokkaido, Yamagata, Fukushima, Tochigi, Ibaraki, Tokyo, Kanazawa, Osaka, Fukuoka, Miyazaki and Okinawa) and took part in the annual health check program in 2005. The glomerular filtration rate (GFR) of each participant was computed from the serum creatinine value using a new equation: GFR (ml/min/1.73 m(2)) = 194 x Age(-0.287) x S-Cr(-1.094) (if female x 0.739). The CKD population nationwide was calculated using census data from 2005. We also recalculated the prevalence of CKD in Japan assuming that the age composition of the population was same as that in the USA. RESULTS: The prevalence of CKD stages 1, 2, 3, and 4 + 5 were 0.6, 1.7, 10.4 and 0.2% in the study population, which resulted in predictions of 0.6, 1.7, 10.7 and 0.2 million patients, respectively, nationwide. The prevalence of low GFR was significantly higher in the hypertensive and proteinuric populations than it was in the populations without proteinuria or hypertension. The prevalence rate of CKD in Japan was similar to that in the USA when the Japanese general population was age adjusted to the US 2005 population estimate. CONCLUSION: About 13% of the Japanese adult population-approximately 13.3 million people-were predicted to have CKD in 2005.

Percutaneous Endoscopic Gastrostomy Tube Removal for Patients With Advanced Dementia: Case Series Study.

BACKGROUND: Although the notion of percutaneous endoscopic gastrostomy (PEG) tube placement for patients with dementia has been changing, the number of cases of PEG placement remains high as Japan has become a super-aged society. However, there is insufficient research about the clinical course of dementia patients with PEG, especially regarding PEG extubation after regaining full oral intake. This case series aimed to reveal the demographic data of patients who successfully underwent PEG extubation and to identify clinical factors that might help predict eventual resumption. METHODS: This retrospective case series was identified in a private, community-based long-term care hospital in Sapporo, Japan. Inclusion criteria for the series were: 1) age, ≥75 years, 2) diagnosis of any type of dementia, and 3) resumption of full oral intake after removal of PEG tubes. RESULTS: Eight female patients were identified. Decreased oral intake was triggered by acute medical conditions, such as infectious enteritis. A trial of oral intake was initiated mostly by speech therapists. A majority of the patients ate pureed food. The patients aged ≥85 years with advanced dementia could be weaned from PEG tubes. CONCLUSION: The series indicates that even patients with limited life expectancy could recover swallowing function by receiving appropriate guidance and care. Constant evaluation for swallowing function even after PEG insertion may be important for PEG extubation.

Slower decline of glomerular filtration rate in the Japanese general population: a longitudinal 10-year follow-up study.

The prevalence of stage 3 to 5 chronic kidney disease (CKD) in Japan (18.7%) is considerably higher than that in the United States (4.5%). This study investigated in the Japanese general population whether this higher prevalence of CKD might reflect to a progressive decline of renal function, and in turn to the increased risk of end-stage renal disease. A decline in renal function over 10 years was examined in 120,727 individuals aged 40 years or older who participated in the annual health examination program of the two periods over 10 years, 1988-1993 and 1998-2003. Renal function was assessed with estimated glomerular filtration rate (GFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation modified by a Japanese coefficient. The rate of GFR decline in the participants was 0.36 mL/min/1.73 m2/year on average. In the male population aged 50-79, the mean rate of GFR decline was significantly higher in the presence of hypertension than in its absence. The rate of GFR decline was more than two times higher in participants with proteinuria than in those without proteinuria in both sexes. The rate was significantly higher in participants with an initial GFR<50 mL/min/1.73 m2 among the groups younger than age 70 and in participants with an initial GFR<40 mL/min/1.73 m2 in the group with age 70-79. Based on the slow rate of GFR decline, we concluded that the decline in renal function progresses slowly in the Japanese general population. Hypertension, proteinuria and lower GFR were found to be significant risk factors for a faster decline of GFR.

Visceral obesity in Japanese patients with metabolic syndrome: reappraisal of diagnostic criteria by CT scan.

To reappraise the cutoff level of abdominal circumference (AC) for diagnosis of visceral obesity in Japanese, we examined the association of visceral fat deposition with other constituents of metabolic syndrome and atherosclerotic cardiovascular disease (ASCD). CT was used for determination of visceral-fat area (VFA), subcutaneous-fat area (SFA) and AC on CT (AC(CT)) in 420 Japanese patients with (n=180) or without ASCD (n=240). VFA cutoff levels were calculated by receiver operating characteristic (ROC) analysis. AC(CT) correlated with VFA (r=0.828), SFA (r=0.795), and AC measured with an anthropometric tape (AC(M), r=0.96). The VFA cutoff levels yielding the maximum sensitivity and specificity to predict two or more components of metabolic syndrome were 92 cm(2) in males and 63 cm(2) in females, which correspond to AC(M) values of 83 cm and 78 cm, respectively. The male AC(M) cutoff level was similar to the AC in current Japanese criteria (85 cm), but the female AC(M) cutoff level was considerably smaller than the criteria, and this change in cutoff level increased the prevalence of metabolic syndrome in females three-fold. The cutoff levels of VFA for predicting presence of ASCD were 98 cm(2) in males and 75 cm(2) in females, corresponding to AC(M) values of 84 cm and 80 cm, respectively. The present results obtained by CT support the validity of the current Japanese criteria for visceral obesity in males but not in females. AC(M) of 78 cm appears to be a cutoff level suitable for diagnosing visceral obesity in Japanese females, though further confirmation is needed.

Noninvasive assessment of left atrial function by strain rate imaging in patients with hypertension: a possible beneficial effect of renin-angiotensin system inhibition on left atrial function.

Renin-angiotensin system (RAS) inhibitors are likely to reduce the development of atrial fibrillation by preventing atrial fibrosis. Strain rate (SR) imaging is a novel echocardiographic technique to quantify left atrial (LA) function. However, it has not been determined whether SR imaging is applicable for detection of LA dysfunction in hypertensive (HT) patients. We used SR imaging to assess alteration in LA function in HT patients and its modification by RAS inhibitors. SR imaging was performed in 80 HT patients and 50 age-matched normotensive (NT) subjects. HT patients were divided into two groups according to left ventricular hypertrophy (LVH) and LA dilatation. Peak SR was measured at each LA segment (septal, lateral, posterior, anterior, and inferior) and mean peak systolic SR (SR-LAs) was calculated by averaging data in each segment. Mean SR-LAs levels in the dilated LA group (1.97+/-0.45 s(-1), n=25) and non-dilated LA group (2.15+/-0.57 s(-1), n=55) were significantly (p<0.05) lower than that in NT subjects (2.53+/-0.71 s(-1)). Irrespective of the presence or absence of LVH, mean SR-LAs in HT patients was lower than that in NT subjects. When RAS inhibitors were used, the mean SR-LAs level in the non-dilated LA group was equivalent to that in NT subjects. In HT patients, mean SR-LAs, an index of LA reservoir function, decreases before development of LA enlargement and LVH. Treatment with RAS inhibitors appears to preserve LA reservoir function in HT patients without dilated LA. SR imaging can detect LA dysfunction in HT patients and is useful for evaluation of the therapeutic benefit on LA reservoir function.

Quadricuspid aortic valve associated with aortic stenosis and regurgitation: report of a case and a review of the literature.

Quadricuspid aortic valve (QAV) is a rare congenital heart valve disease, and more than half of QAV patients have severe aortic regurgitation (AR). We describe the case of a 66-year-old woman with QAV detected by transthoracic echocardiography during a medical checkup. Doppler echocardiographic examination showed mild aortic stenosis and mild AR. The patient has been under routine medical review without medication therapy. At follow-up echocardiographic examinations over a 4-year period, no significant changes in severity of aortic stenosis or AR were found. The clinical and functional characteristics of 192 cases of QAV were reviewed. The functional status of the QAV was known in 144 cases; of these, only 13 (9%) had both aortic stenosis and AR.

Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.

Effects of angiotensin II type 1 receptor gene polymorphisms on insulin resistance in a Japanese general population: the Tanno-Sobetsu study.

Although gene polymorphisms in the renin-angiotensin system (RAS) are predisposing factors for cardiovascular diseases, the precise mechanisms and interactions among confounding factors have not been clarified. We investigated whether genetic variants of RAS are involved in insulin sensitivity in a Japanese general population. During a medical checkup in 2001, participants (n=550) were recruited from among the residents of the towns of Tanno and Sobetsu, and written informed consent was obtained to participate in the genetic analysis and the epidemiological study. The insertion/deletion (lID) polymorphism of the angiotensin-converting enzyme gene (ACE), the Met235Thr polymorphism of the angiotensinogen gene (AGT), and the A1166C polymorphism of the angiotensin II type 1 receptor gene (AGTR1) were determined by gel electrophoresis or the TaqMan PCR method. We assessed insulin sensitivity using the homeostasis model assessment insulin resistance (HOMA-IR). The RAS gene polymorphisms were not associated with log-transformed values of HOMA-IR, whereas borderline association (p=0.02) was found between the A1166C polymorphism and dichotomous categorization of insulin resistance (defined as HOMA-IR > or =1.73). Our results suggested that the A1166C polymorphism of AGTR1 might affect insulin resistance by altering the responsiveness to angiotensin II signaling, though this mechanism is as yet inconclusive. Further study is required to confirm these findings in a larger, multi-ethnic population.

Bradykinin release and inactivation in brain of rats submitted to an experimental model of Alzheimer's disease.

The kallikrein-kinin system is involved in a variety of physiological and pathological processes. Components of this system, identified in rat and human brains, can be altered in neurodegenerative processes such as Alzheimer's disease. Here, we studied kinin release and its inactivation in rats submitted to chronic cerebroventricular infusion of beta-amyloid (Abeta) peptide. Neurodegeneration was confirmed by histological analysis of brain samples. In cerebrospinal fluid of animals infused with Abeta, bradykinin concentration was increased, as determined by radioimmunoassay. However, in the brain of Abeta group, we only detected the tripeptide Arg-Pro-Pro, purified by reversed-phase chromatography and characterized by liquid chromatography-electrospray ionization mass spectrometry. This fragment of bradykinin indicated the possible participation of kinin-processing enzymes in the brain such as a prolyl oligopeptidase.

Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies.

BACKGROUND: The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection. METHODS: The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated. RESULTS: In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months. CONCLUSIONS: HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.

Liddle's syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit.

Liddle's syndrome is an autosomal dominant form of salt-sensitive hypertension and has been shown to be caused by missense or frameshift mutations in the amiloride-sensitive epithelial sodium channel (ENaC), which is composed of three subunits: alpha, beta, and gamma. All disease mutations either remove or alter amino acids of the target proline-rich PPPxY sequence (PY motif) of beta- or gamma-ENaC and result in increased channel activity. In this report, we present a family with Liddle's syndrome whose abnormality is caused by a novel missense mutation, P616R, in the PY motif of the betaENaC. Functional studies using the P616R mutant expressed in Xenopus oocytes showed an approximately 6-fold increase in the amiloride-sensitive sodium channel activity compared with that of the wild type. These findings provide additional clinical evidence that a conserved PY motif is critically important for the regulation of ENaC activity.