Nighttime Blood Pressure Phenotype and Cardiovascular Prognosis: Practitioner-Based Nationwide JAMP Study.

BACKGROUND: Ambulatory and home blood pressure (BP) monitoring parameters are better predictors of cardiovascular events than are office BP monitoring parameters, but there is a lack of robust data and little information on heart failure (HF) risk. The JAMP study (Japan Ambulatory Blood Pressure Monitoring Prospective) used the same ambulatory BP monitoring device, measurement schedule, and diary-based approach to data processing across all study centers and determined the association between both nocturnal hypertension and nighttime BP dipping patterns and the occurrence of cardiovascular events, including HF, in patients with hypertension. METHODS: This practitioner-based, nationwide, multicenter, prospective, observational study included patients with at least 1 cardiovascular risk factor, mostly hypertension, and free of symptomatic cardiovascular disease at baseline. All patients underwent 24-hour ambulatory BP monitoring at baseline. Patients were followed annually to determine the occurrence of primary end point cardiovascular events (atherosclerotic cardiovascular disease and HF). RESULTS: A total of 6,359 patients (68.6±11.7 years of age, 48% men) were included in the final analysis. During a mean±SD follow-up of 4.5±2.4 years, there were 306 cardiovascular events (119 stroke, 99 coronary artery disease, 88 HF). Nighttime systolic BP was significantly associated with the risk of atherosclerotic cardiovascular disease and HF (hazard ratio adjusted for demographic and clinical risk factors per 20-mm Hg increase: 1.18 [95% CI, 1.02-1.37], P=0.029; and 1.25 [95% CI, 1.00-1.55], P=0.048, respectively). Disrupted circadian BP rhythm (riser pattern, nighttime BP higher than daytime BP) was significantly associated with higher overall cardiovascular disease risk (1.48 [95% CI, 1.05-2.08]; P=0.024), and especially HF (2.45 [95% CI, 1.34-4.48]; P=0.004) compared with normal circadian rhythm. CONCLUSIONS: Nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, in particular for HF. These findings suggest the importance of antihypertensive strategies targeting nighttime systolic BP. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000020377.

Twenty-Four-Hour Blood Pressure-Lowering Effect of a Sodium-Glucose Cotransporter 2 Inhibitor in Patients With Diabetes and Uncontrolled Nocturnal Hypertension: Results From the Randomized, Placebo-Controlled SACRA Study.

BACKGROUND: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. METHODS: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). RESULTS: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m2). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (-6.3 mm Hg; P=0.004); between-group difference in change from baseline was -4.3 mm Hg (P=0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (-9.5, -7.7, -7.5, and -8.6 mm Hg, respectively; all P≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (-1.3 kg and -0.33%; both P<0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (-12.1%; P=0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (-8.2% [P=0.008] and -9.7% [P=0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. CONCLUSIONS: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. CLINICAL TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT03050229.

Intensive uric acid-lowering therapy in CKD patients: the protocol for a randomized controlled trial.

BACKGROUND: Hyperuricemia would be a risk factor for the development/progression of CKD. However, several studies showed U-shape association between serum uric acid level and renal impairment, suggesting that hypouricemia was rather associated with renal dysfunction. Perhaps, there is the optimal target level of serum UA for renal function. METHODS: The Target-UA study is a multicenter randomized controlled trial. Eligible CKD patients (eGFR ≥ 30, < 60 mL/min/1.73 m2 and urine protein < 0.5 g/gCr or urine albumin to creatinine ratio (ACR) < 300 mg/gCr) with serum UA ≥ 8.0 mg/dL (≥ 7.0 mg/dl: under the treatment) will be enrolled and be randomly assigned to the intensive therapy group (target serum UA level ≥ 4.0 mg/dL, < 5.0 mg/dL) or the standard therapy group (serum UA level ≥ 6.0 mg/dL, < 7.0 mg/dL). Topiroxostat, a new xanthine oxidase inhibitor, will be administered to treat hyperuricemia. The primary endpoint is a change in logarithmic value of urine ACR between baseline and week 52 of treatment. The secondary endpoints include changes in serum UA, eGFR, urine protein, lipid profile, and onset of composite cardiovascular events, renal events, gouty arthritis, and attack of urolithiasis. The number of subjects has been set to be 185 in each group for a total of 370. DISCUSSION: This is the first study, to the best of our knowledge, to determine the optimal target level of serum UA for renal protection and is expected to lead to progress in CKD treatment. TRIAL REGISTRATION: (UMIN000026741 and jRCTs051180146).

Protein-Truncating Variants at the Cholesteryl Ester Transfer Protein Gene and Risk for Coronary Heart Disease.

RATIONALE: Therapies that inhibit CETP (cholesteryl ester transfer protein) have failed to demonstrate a reduction in risk for coronary heart disease (CHD). Human DNA sequence variants that truncate the CETP gene may provide insight into the efficacy of CETP inhibition. OBJECTIVE: To test whether protein-truncating variants (PTVs) at the CETP gene were associated with plasma lipid levels and CHD. METHODS AND RESULTS: We sequenced the exons of the CETP gene in 58 469 participants from 12 case-control studies (18 817 CHD cases, 39 652 CHD-free controls). We defined PTV as those that lead to a premature stop, disrupt canonical splice sites, or lead to insertions/deletions that shift frame. We also genotyped 1 Japanese-specific PTV in 27561 participants from 3 case-control studies (14 286 CHD cases, 13 275 CHD-free controls). We tested association of CETP PTV carrier status with both plasma lipids and CHD. Among 58 469 participants with CETP gene-sequencing data available, average age was 51.5 years and 43% were women; 1 in 975 participants carried a PTV at the CETP gene. Compared with noncarriers, carriers of PTV at CETP had higher high-density lipoprotein cholesterol (effect size, 22.6 mg/dL; 95% confidence interval, 18-27; P<1.0×10-4), lower low-density lipoprotein cholesterol (-12.2 mg/dL; 95% confidence interval, -23 to -0.98; P=0.033), and lower triglycerides (-6.3%; 95% confidence interval, -12 to -0.22; P=0.043). CETP PTV carrier status was associated with reduced risk for CHD (summary odds ratio, 0.70; 95% confidence interval, 0.54-0.90; P=5.1×10-3). CONCLUSIONS: Compared with noncarriers, carriers of PTV at CETP displayed higher high-density lipoprotein cholesterol, lower low-density lipoprotein cholesterol, lower triglycerides, and lower risk for CHD.

Genome-wide association study for white coat effect in Japanese middle-aged to elderly people: The HOMED-BP study.

BACKGROUND: White coat effect (WCE), the blood pressure (BP) difference between clinical and non-clinical settings, can lead to clinical problems such as misdiagnosis of hypertension. Etiology of WCE has been still unclear, especially from genetic aspects. The present article investigated association between genome-wide single nucleotide polymorphisms (SNPs) and WCE in patients with essential hypertension. METHODS: The present cross-sectional analyses were based on 295 Japanese essential hypertensive outpatients aged ≧40 years enrolled in randomized control study, Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure (HOMED-BP) study, who were not taking antihypertensive medications before the randomization. Home and clinic BP were measured. WCE was defined by subtracting home BP from clinic BP. Genotyping was conducted with 500K DNA microarray chips. Association between genome-wide SNPs and WCE were analyzed. For replication (p < 10-4), we analyzed participants from Ohasama study who took no antihypertension medications and whose SNPs were collected. RESULTS: Genome-wide SNPs were not significantly associated with WCE of systolic and diastolic BP after corrections of multiple comparisons (p < 2 × 10-7). We found suggestive SNPs associated with WCE of systolic and diastolic BP (p < 10-4). However, the consistent results were not obtained in the replication study. CONCLUSION: The present article showed no significant association between genome-wide SNPs and WCE. Since there were several suggestive SNPs associated with WCE, the present study warrants a further study with bigger sample size for investigating the genetic influence on WCE.

Comparative Effects of an Angiotensin II Receptor Blocker (ARB)/Diuretic vs. ARB/Calcium-Channel Blocker Combination on Uncontrolled Nocturnal Hypertension Evaluated by Information and Communication Technology-Based Nocturnal Home Blood Pressure Monitoring　- The NOCTURNE Study.

BACKGROUND: Nocturnal blood pressure (BP) is an independent risk factor of cardiovascular events. The NOCTURNE study, a multicenter, randomized controlled trial (RCT) using our recently developed information and communication technology (ICT) nocturnal home BP monitoring (HBPM) device, was performed to compare the nocturnal HBP-lowering effects of differential ARB-based combination therapies in 411 Japanese patients with nocturnal hypertension (HT).Methods and Results:Patients with nocturnal BP ≥120/70 mmHg at baseline even under ARB therapy (100 mg irbesartan daily) were enrolled. The ARB/CCB combination therapy (irbesartan 100 mg+amlodipine 5 mg) achieved a significantly greater reduction in nocturnal home systolic BP (primary endpoint) than the ARB/diuretic combination (daily irbesartan 100 mg+trichlormethiazide 1 mg) (-14.4 vs. -10.5 mmHg, P<0.0001), independently of urinary sodium excretion and/or nocturnal BP dipping status. However, the change in nocturnal home systolic BP was comparable among the post-hoc subgroups with higher salt sensitivity (diabetes, chronic kidney disease, and elderly patients). CONCLUSIONS: This is the first RCT demonstrating the feasibility of clinical assessment of nocturnal BP by ICT-nocturnal HBPM. The ARB/CCB combination was shown to be superior to ARB/diuretic in patients with uncontrolled nocturnal HT independently of sodium intake, despite the similar impact of the 2 combinations in patients with higher salt sensitivity.

Heterogeneous effects of association between blood pressure loci and coronary artery disease in east Asian individuals.

BACKGROUND: A coronary artery disease (CAD) association study of genetic loci previously identified as being associated with blood pressure (BP) was performed in east Asian populations. METHODS AND RESULTS: Nine single nucleotide polymorphisms (SNPs) from 9 candidate loci robustly confirmed to be associated with BP in east Asian people, were genotyped. Genotyping was done in up to 17,785 CAD case-control samples (6,522 cases and 11,263 controls). We then tested the associations with other metabolic traits (n≤17,900) and with type 2 diabetes (931 cases and 1,404 controls), and looked up the datasets in silico in other populations. Significant (adjusted P<0.05) CAD associations were found for 5 BP loci: 3 new CAD associations at FIGN,FGF5 and NPR3, and 2 previously reported ones at ATP2B1 and CNNM2. The strongest CAD association was detected at ATP2B1rs2681472 (P=1.7×10(-8)), in the direction inverted to what is generally recognized for BP in the epidemiological studies.CNNM2rs12413409 showed significant association with CAD (P=8.7×10(-7)) and BMI (P=3.5×10(-8), when meta-analyzed with 75,807 east Asian people). The genetic risk score combining BP-raising alleles at each of the SNPs was positively associated with CAD (P=0.011). CONCLUSIONS: A substantial proportion of genetic variants associated with BP were also associated with the risk of CAD in east Asian people, and there was some counter-evidence for causal inference.

Validity of salt intake assessment system based on a 24-h dietary recall method using a touch panel computer.

BACKGROUND: An electronic system for salt intake assessment using a 24-h dietary recall method has been developed in Japan. We evaluated the validity of this salt intake system for assessing salt intake. METHODS: We prospectively obtained data on estimated salt intake using 24-hour urinary sodium excretion (24-hUNaCl) and salt intake by the salt intake assessment system from 203 consecutive outpatients with essential hypertension (age: 67.8 ± 10.7 years; 53.7% men). RESULTS: Mean values were 9.7 ± 2.9 g/day for 24-hUNaCl and 9.1 ± 2.9 g/day for the salt intake assessment system before corrections. The salt intake estimated by the present system was significantly correlated with 24-hUNaCl (r = 0.66, p < 0.0001). After corrections for habitual use of discretionary seasonings, habitual intake of salty foods, and physical activity, correlation coefficients between salt intake and 24-hUNaCl increased from 0.60 to 0.66 in men <65 years, from 0.80 to 0.81 in men ≥ 65 years, from 0.64 to 0.75 in women <65 years, and from 0.52 to 0.59 in women ≥ 65 years. After further correction for regional differences in average salt intake, the correlation coefficient reached 0.72 in all patients. CONCLUSION: After correction for dietary habits, lifestyle factors, and differences in average salt intake by region, this system may be a useful tool in Japan to encourage salt restriction in the clinical treatment of hypertension and improve public health in terms of salt restriction overall.

Exploratory study on the relationship between urinary sodium/potassium ratio, salt intake, and the antihypertensive effect of esaxerenone: the ENaK Study.

Excessive salt intake is one of the causes of hypertension, and reducing salt intake is important for managing the risk of hypertension and subsequent cardiovascular events. Esaxerenone, a mineralocorticoid receptor blocker, has the potential to exert an antihypertensive effect in hypertensive patients with excessive salt intake, but evidence is still lacking, especially in clinical settings. We aimed to determine if baseline sodium/potassium ratio and baseline estimated 24-h urinary sodium excretion can predict the antihypertensive effect of esaxerenone in patients with essential hypertension inadequately controlled with an angiotensin receptor blocker (ARB) or a calcium channel blocker (CCB). This was an exploratory, open-label, interventional study with a 4-week observation period and a 12-week treatment period. Esaxerenone was orally administered once daily in accordance with the Japanese package insert. In total, 126 patients met the eligibility criteria and were enrolled (ARB subcohort, 67; CCB subcohort, 59); all were included in the full analysis set (FAS) and safety analysis. In the FAS, morning home systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from baseline to end of treatment (primary efficacy endpoint) (-11.9 ± 10.9/ - 6.4 ± 6.8 mmHg, both p < 0.001); a similar trend was observed in both subcohorts. Significant reductions were also shown in bedtime home and office SBP/DBP (all p < 0.001). Each BP change was consistent regardless of the urinary sodium/potassium ratio or estimated 24-h urinary sodium excretion at baseline. The urinary albumin-creatinine ratio (UACR) and N-terminal pro-brain natriuretic peptide (NT-proBNP) significantly decreased from baseline to Week 12 in the total population and both subcohorts. No new safety concerns were raised. Esaxerenone significantly decreased morning home, bedtime home, and office BP; UACR; and NT-proBNP in this patient population, regardless of concomitant ARB or CCB use. The antihypertensive effect of esaxerenone was independent of the urinary sodium/potassium ratio and estimated 24-h urinary sodium excretion at baseline.

-374 T/A polymorphism in RAGE gene is associated with onset of diabetes mellitus, atherosclerosis, and renal dysfunction in patients with hypertension.

Receptor of advanced glycation end products (RAGE) is reportedly linked with chronic inflammatory diseases due to aging or diabetes. The aim of this study was to show how -374 T/A RAGE has an impact on systemic vascular damage and renal function. The study subjects were a total of 468 essential hypertension patients from the Non-Invasive Atherosclerotic Evaluation in Hypertension (NOAH) study cohort. We prospectively examined the association of -374 T/A RAGE with their prognoses and investigated the correlation between -374 T/A RAGE and multiple clinical parameters. Kaplan-Meier analysis did not show a significant association of -374 T/A RAGE with total mortality or the prevalence of cardiovascular events. Carriers of the A allele showed a significantly higher prevalence of diabetes mellitus (DM) and lower estimated glomerular filtration rate (eGFR) than subjects without this allele. In subjects with DM, carriers of the A allele showed a significantly lower eGFR. These significant correlations were only seen in male subjects. Carriers of the A allele of -374 T/A RAGE show an independent risk of atherosclerosis and reduced renal function in male hypertensive patients with DM.

Rationale and design of a multicenter randomized study comparing the efficacy and safety of esaxerenone versus trichlormethiazide in patients with uncontrolled essential hypertension: EXCITE-HT study.

The next-generation mineralocorticoid receptor blocker (MRB) esaxerenone has favorable antihypertensive effects in patients who do not respond to treatment with first-line antihypertensive agents and may be beneficial as a second-line treatment. However, MRBs are currently considered a fourth-line treatment as there is no clinical evidence comparing the efficacy of esaxerenone with other classes of antihypertensive agents. The multicenter, randomized, open-label, parallel-group EXCITE-HT study will evaluate the efficacy and safety of esaxerenone as a second-line agent in the treatment of Japanese patients with uncontrolled essential hypertension. After a 4-week run-in period, patients will receive either esaxerenone or trichlormethiazide for 12 weeks per the package insert and the Japanese Society of Hypertension Guidelines for the Management of Hypertension. At Weeks 4 and 8, the dose of esaxerenone or trichlormethiazide may be increased. Blood pressure (home [morning and bedtime] and office), serum biomarkers, and urinary biomarkers will be measured. The primary efficacy endpoint is the change from baseline in morning home systolic blood pressure/diastolic blood pressure to the end of treatment. The EXCITE-HT study is expected to validate the non-inferiority of esaxerenone to trichlormethiazide and provide the first evidence for the early use of esaxerenone as a second-line agent in the treatment of Japanese patients with uncontrolled essential hypertension instead of its current use as a fourth-line agent.

Nighttime hemodynamic phenotype. A novel risk factor for cardiovascular disease, especially heart failure: the practitioner-based nationwide JAMP study.

BACKGROUND: Non-dipper and riser patterns of nocturnal blood pressure (BP) are risk factors for cardiovascular disease (CVD), including heart failure (HF). However, the risk associated with a disrupted nocturnal pattern of heart rate is not well known. OBJECTIVES: To investigate whether the nighttime heart rate is a risk factor for HF, alongside nighttime BP phenotype. METHODS: The practitioner-based, nationwide, prospective Japan Ambulatory Blood Pressure Monitoring Prospective (JAMP) study included patients with ≥ 1 CVD risk factor but without symptomatic CVD at baseline. All patients underwent 24-h ambulatory BP monitoring at baseline and were followed annually. Nocturnal heart rate dipping (%) was calculated as 100•[1 - nighttime/daytime heart rate]. RESULTS: During a mean 4.5 years' follow-up in 6,359 patients (mean age 68.6 years), there were 306 CVD events (119 stroke, 99 coronary artery disease, and 88 HF). A 10-beats/min increase in nighttime heart rate was significantly associated with a 36-47% increase in the risk of total CVD, stroke and HF events independently of office SBP and nighttime SBP (all p < 0.005). The CVD and HF risk associated with nocturnal heart rate dipping status was independent of office and 24-h systolic BP and nocturnal BP dipping status (p < 0.001). Performance of the final model for predicting HF including BP parameters was significantly improved by the addition of nocturnal heart rate dipping patterns (p = 0.038; C-statistic 0.852). CONCLUSION: Nighttime non-dipper and riser patterns of heart rate were associated with CVD especially HF, independently and additively of nocturnal BP dipping status, indicating the importance of antihypertensive strategies targeting nighttime hemodynamics. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000020377.

Cross-sectional survey of hypertension management in clinical practice in Japan: the Kanagawa Hypertension Study 2021 conducted in collaboration with Japan Medical Association Database of Clinical Medicine.

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.

Inconsistent Control Status of Office, Home, and Ambulatory Blood Pressure All Taken Using the Same Device: The HI-JAMP Study Baseline Data.

BACKGROUND: Inconsistencies between the office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. METHODS: We studied consistency in the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated "all-in-one" BP monitoring device. In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-hour ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), for a total of seven BP measurement days. RESULTS: Using the thresholds of the JSH2019 and ESC2018 guidelines, the patients with consistent classification of well-controlled status in the office (<140 mmHg) and home systolic BP (SBP) (<135 mmHg) (n = 970) also tended to have well-controlled 24-hour SBP (<130 mmHg) (n = 808, 83.3%). The patients with the consistent classification of uncontrolled status in office and home SBP (n = 579) also tended to have uncontrolled 24-hour SBP (n = 444, 80.9%). Among the patients with inconsistent classifications of office and home BP control (n = 803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds were applied as an alternative, the results were essentially the same. CONCLUSIONS: The combined assessment of the office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

CVD-associated non-coding RNA, ANRIL, modulates expression of atherogenic pathways in VSMC.

ANRIL is a newly discovered non-coding RNA lying on the strongest genetic susceptibility locus for cardiovascular disease (CVD) in the chromosome 9p21 region. Genome-wide association studies have been linking polymorphisms in this locus with CVD and several other major diseases such as diabetes and cancer. The role of this non-coding RNA in atherosclerosis progression is still poorly understood. In this study, we investigated the implication of ANRIL in the modulation of gene sets directly involved in atherosclerosis. We designed and tested siRNA sequences to selectively target two exons (exon 1 and exon 19) of the transcript and successfully knocked down expression of ANRIL in human aortic vascular smooth muscle cells (HuAoVSMC). We used a pathway-focused RT-PCR array to profile gene expression changes caused by ANRIL knock down. Notably, the genes affected by each of the siRNAs were different, suggesting that different splicing variants of ANRIL might have distinct roles in cell physiology. Our results suggest that ANRIL splicing variants play a role in coordinating tissue remodeling, by modulating the expression of genes involved in cell proliferation, apoptosis, extra-cellular matrix remodeling and inflammatory response to finally impact in the risk of cardiovascular disease and other pathologies.

Poor glycemic control rather than types of diabetes is a risk factor for sarcopenia in diabetes mellitus: The MUSCLES-DM study.

AIMS/INTRODUCTION: Though poor glycemic control and insulin treatment are reported to be associated with sarcopenia in type 2 diabetes, type 1 diabetes may be a stronger risk for sarcopenia. We therefore studied the effect of the type of diabetes, glycemic control, and insulin therapy on the prevalence and characteristics of sarcopenia. MATERIALS AND METHODS: A total of 812 Japanese patients with diabetes (type 1: n = 57; type 2: n = 755) were enrolled in this study. Sarcopenia was defined as low handgrip strength or slow gait speed and low appendicular skeletal muscle mass. RESULTS: Among participants aged ≥65 years, the sarcopenia prevalence rate was higher among patients with type 1 diabetes (20.0%) than among those with type 2 diabetes (8.1%). The prevalence rate of low handgrip strength was higher in type 1 diabetes (50.0%) than in type 2 diabetes (28.7%). In logistic regression analysis, type 1 diabetes was significantly associated with the prevalence of low handgrip strength. In logistic regression analysis, medication with insulin was significantly associated with the prevalence of sarcopenia; this association was not retained after adjusting for HbA1c. CONCLUSIONS: The prevalence of sarcopenia in older adult patients was higher in those with type 1 diabetes than in those with type 2 diabetes. Among the components of sarcopenia, the difference was most prominent in the frequency of low handgrip strength. Poor glycemic control rather than type of diabetes or insulin treatment was revealed to be a primary risk factor for sarcopenia in diabetes mellitus.

Direct comparison of the reproducibility of in-office and self-measured home blood pressures.

OBJECTIVE: The aim was to compare short-term and long-term reproducibilities of in-office unattended blood pressure (BP), namely automated office blood pressure (AOBP), conventionally measured attended office BP, and self-measured home BP. METHODS: A multicentre, clinical study was conducted in Japan, and 287 Japanese outpatients on antihypertensive drug medication were followed-up for 1 year. RESULTS: The intensity of drug treatment was sustained consistently throughout the study period (defined daily doses, 1.62-1.68; P = 0.12). The mean SBP differences between baseline and 1 month later, as well as baseline and 1 year later, were less than 1.5 mmHg, whereas the standard deviations of the differences for home, AOBP, and attended office measurements for the 1-year interval were 7.7, 14.5, and 15.3 mmHg, respectively. The coefficients of variation were significantly smaller for home BP than for AOBP among all patients at both 1-month and 1-year intervals (P < 0.0001). In the 1-month interval, partial correlation coefficients of home BP (r, 0.73/0.88 for systolic/diastolic measures) were significantly higher than of conventional BP (r, 0.47/0.69). However, the correlations converged to the modest level regardless of BP information (r, 0.49-0.54/0.63-0.73) when the 1-year interval was assessed. Results were confirmatory when patients on the same drug regimen (n = 167) were analysed. CONCLUSION: A higher reproducibility of home BP was demonstrated compared with in-office BP, including AOBP. However, the modest correlations for the 1-year interval support the importance of regular assessment of BP, regardless of in-office or home measurements for treatment of hypertension.

Japan Geriatrics Society "Statement for the use of telemedicine in geriatric care: Telemedicine as a complement to in-person medical practice": Geriatric Medical Practice Committee consensus statement.

Telemedicine has changed from a way to treat patients with limited access to hospitals to a necessary method of treatment for non-urgent conditions during the coronavirus disease 2019 pandemic. There are two styles of telemedicine, namely "hybrid medical care" and "gateway medical care," which take advantage of the characteristics of online medical care and might become important in the near future. During hybrid medical care, a patient and their primary care physician have face-to-face medical care while simultaneously being examined by a specialist physician through telemedicine, leading to an overall improvement in the level of local medical care and expansion in the number of treatable diseases. Gateway medical practice is a form of telemedicine used for patients who would otherwise refuse or not receive in-person medical care to engage in consultation with a physician. Telemedicine allows physicians to determine disease severity and triage patients, while reducing unnecessary home visits, emergency hospitalizations and the spread of infection. Telemedicine is less intense than in-person medical care, and allows for easier collaboration with other healthcare providers. However, telemedicine is not optimal for conditions requiring a definitive diagnosis and a comprehensive understanding of the patient's medical history. It is limited by the patient's ability to use telemedicine devices, and the risk of accidental treatments and fraud. The use of telemedicine might result in the development of new, online comprehensive geriatric assessment tools and technologies. Geriatr Gerontol Int 2022; 22: 913-916.

Blood pressure and hypertension are associated with 7 loci in the Japanese population.

BACKGROUND: Two consortium-based genome-wide association studies have recently identified robust and significant associations of common variants with systolic and diastolic blood pressures in populations of European descent, warranting further investigation in populations of non-European descent. METHODS AND RESULTS: We examined the associations at 27 loci reported by the genome-wide association studies on Europeans in a screening panel of Japanese subjects (n=1526) and chose 11 loci showing association signals (1-tailed test in the screening, P<0.3) for an extensive replication study with a follow-up panel of 3 Japanese general-population cohorts (n < or =24 300). Significant associations were replicated for 7 loci-CASZ1, MTHFR, ITGA9, FGF5, CYP17A1-CNNM2, ATP2B1, and CSK-ULK3-with any or all of these 3 traits: systolic blood pressure (P=1.4x10(-14) to 0.05), diastolic blood pressure (P=1.9x10(-12) to 0.05), and hypertension (P=2.0x10(-14) to 0.006; odds ratio, 1.10 to 1.29). The strongest association was observed for FGF5. In the whole study panel, the variance (R(2)) for blood pressure explained by the 7 single-nucleotide polymorphism loci was calculated to be R(2)=0.003 for male and 0.006 for female participants. Stratified analysis implied the potential presence of a gene-age-sex interaction, although it did not reach a conclusive level of statistical significance after adjustment for multiple testing. CONCLUSIONS: We have confirmed 7 loci associated with blood pressure and/or hypertension in the Japanese. These loci can guide fine-mapping efforts to pinpoint causal variants and causal genes with the integration of multiethnic results.

Confirmation of ALDH2 as a Major locus of drinking behavior and of its variants regulating multiple metabolic phenotypes in a Japanese population.

BACKGROUND: Normative alcohol use (or drinking behavior) influences the risk of cardiovascular disease in a multi-faceted manner. To identify susceptibility gene variants for drinking behavior, a 2-staged genome-wide association study was performed in a Japanese population. METHODS AND RESULTS: In the stage-1 scan, 733 cases and 729 controls were genotyped with 456,827 SNP markers. The associated loci without redundancy of linkage disequilibrium were further examined in the stage-2 general population panel comprising 2,794 drinkers (≥ once per week), 1,521 chance drinkers (< once per week), and 1,351 non-drinkers. Along with genome-wide exploration, we aimed to replicate the trait association of a candidate gene SNP previously reported (rs1229984 in ADH1B). A cluster of 12 SNPs on 12q24 were found to significantly (P<5×10(-8)) associate with drinking behavior in stage 1, among which rs671 (a Glu-to-Lys substitution at position 504) in the ALDH2 gene showed the strongest association (odds ratio (OR)=0.16, P=3.6×10(-211) in the joint analysis). The association was also replicated for rs1229984 (OR=1.20, P<3.6×10(-4)). Furthermore, ALDH2 504Lys was associated with several metabolic traits, eg, lower levels of high-density lipoprotein cholesterol and liver enzymes-AST, ALT, and γGTP-by interacting with alcohol intake. CONCLUSIONS: Our results confirm ALDH2 as a major locus regulating drinking behavior in the Japanese, indicating that the ALDH2 504Lys variant exerts pleiotropic effects on risk factors of cardiovascular disease among drinkers.