IMPORTANCE:The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown. OBJECTIVE:To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control. DESIGN, SETTING, AND PARTICIPANTS:Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent. INTERVENTIONS:In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed. MAIN OUTCOMES AND MEASURES:The primary outcome was stroke recurrence. RESULTS:The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, -1.5%; 95% CI, -2.6% to -0.4%; number needed to treat, 67; 95% CI, 39-250). CONCLUSIONS AND RELEVANCE:Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT01198496.

Background: Lowering of blood pressure after stroke reduces the risk of recurrent stroke, but the optimum target blood pressure level is unknown. We evaluated the effects of intensive versus standard blood-pressure-lowering regimen on the rate of recurrent stroke in patients with recent stroke.

It has been reported that cardiovascular events often occur on Monday morning, especially in the young working population. Because hypertension is a major cardiovascular risk, we examined whether blood pressure was elevated on Monday, especially in the morning during work. However, there were no weekly rhythms in blood pressure itself. Instead, we found significant interactions between the double product (systolic blood pressure × heart rate) and weekly (high on Monday) and circadian (high in the morning) rhythms. Further studies are required to determine whether Monday morning preference in cardiovascular events is caused by increased double product.

Primarily, the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of the proximal tubules to the blood, and excrete glucose into the urine. Therefore, glucose and caloric balances become negative, reducing both the blood glucose level and insulin secretion. On the other hand, the proximal tubular fluid, constituted with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. Under low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, similar to when loop diuretics are given. Subanalysis data on heart failure (HF) from the EMPA-REG OUTCOME trials are discussed, assuming that SGLT2 inhibitors are loop diuretics. Renin-angiotensin system inhibitors and β-blockers contribute to prognostic improvements of HF, independent of SGLT2 inhibitors, and therefore, both regimens are essential for the treatment of HF. On the other hand, the prognostic improvements by SGLT2 inhibitors are not significant under treatment including conventional diuretics such as loop diuretics and aldosterone antagonists, suggesting that the prognostic improvement in HF by SGLT2 inhibitors is mostly through their diuretic action. (Circ J 2016; 80: 2277-2281).

Background Since dyslipidemia has been shown to be an independent risk factor for the progression of chronic kidney disease (CKD), low-density lipoprotein cholesterol (LDL-C)-lowering therapy can be potentially associated with inhibition of CKD progression. The ASsessment of clinical Usefulness in CKD patients with Atorvastatin (ASUCA) trial was designed to determine whether atorvastatin has protective effects on renal function in patients with dyslipidemia and CKD. Methods We decided to carry out a prospective multi-center, open-labeled, randomized trial to compare the reno-protective effects between diet therapy alone and atorvastatin plus diet therapy in patients with dyslipidemia (LDL-C ≥ 140 mg/dL if not treated or LDL-C ≥ 100 mg/dL if treated with lipid-lowering drugs in subjects taking dyslipidemia-treating agents other than statins) and CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 ]. The primary endpoint is the change in eGFR (mL/min/1.73 m 2 ) as calculated by the modified MDRD equation for Japanese after 2 years of treatment. Results Enrollment began in April 2009 and was completed in March 2011. A total of 334 patients (213 male and 121 female) were randomly assigned to either diet therapy alone or atorvastatin plus diet therapy and included in an intent-to-treat population. In the atorvastatin and control groups, the mean ages were 63.2 and 63.1 years, mean eGFRs were 55.9 and 54.0 mL/min/1.73 m 2 , and median urinary albumin/creatinine ratios were 24.9 and 29.1 mg/g, respectively. Conclusions This study distinguishes itself from similar studies by increasing statistical accuracy derived from its significantly larger sample size and longitudinal magnitude. The results of this study will help to determine whether atorvastatin has reno-protective effects in patients with dyslipidemia and CKD.

Primarily the sodium-glucose cotransporter 2 (SGLT2) inhibitors suppress the cotransport of glucose and sodium from the tubular lumen of proximal tubules to the blood and enhance the glucose excretion into urine. Therefore, glucose and caloric balances become negative, making the blood glucose level as well as insulin secretion both reduced. On the other hand, the proximal tubular fluid, constituting with low chloride concentration because of SGLT2 inhibition, is transferred to the loop of Henle. On the low chloride conditions, the reabsorption mechanisms in the loop of Henle do not work, as if loop diuretics are given. Finally, blood pressure is also lowered secondarily due to the loop diuretic action by SGLT2 inhibitions. Thus, the metabolic and hemodynamic combined systems synergistically interact further to suppress the risks leading to atherosclerosis and organs damage. Precise mechanisms for SGLT2 inhibitors to work in various aspects especially in preventing organ damage and cardiovascular events must be clarified further.

The close association between dietary salt and hypertension is well established. However, previous studies generally assessed salt intake without adjustment for body weight. Herein, we investigated the significance of body weight-adjusted salt intake in the general population. The present cross-sectional study included 7629 participants from our yearly physical checkup program, and their salt intake was assessed using a spot urine test to estimate 24-hour urinary salt excretion. Total salt intake increased with increasing body weight. Body weight-adjusted salt intake was greater in participants with hypertension than in those without hypertension. Systolic blood pressure, estimated glomerular filtration rate, and urinary albumin were independently correlated with body weight-adjusted salt intake after adjustment for possible cardiovascular risk factors. Excessive body weight-adjusted salt intake could be related to an increase in blood pressure and hypertensive organ damage. Adjustment for body weight might therefore provide clinically important information when assessing individual salt intake.

Background Although there is a close relationship between dietary sodium and hypertension, the concept that persons with relatively high dietary sodium are at increased risk of developing hypertension compared with those with relatively low dietary sodium has not been studied intensively in a cohort. Methods and Results We conducted an observational study to investigate whether dietary sodium intake predicts future blood pressure and the onset of hypertension in the general population. Individual sodium intake was estimated by calculating 24-hour urinary sodium excretion from spot urine in 4523 normotensive participants who visited our hospital for a health checkup. After a baseline examination, they were followed for a median of 1143 days, with the end point being development of hypertension. During the follow-up period, hypertension developed in 1027 participants (22.7%). The risk of developing hypertension was higher in those with higher rather than lower sodium intake (hazard ratio 1.25, 95% CI 1.04 to 1.50). In multivariate Cox proportional hazards regression analysis, baseline sodium intake and the yearly change in sodium intake during the follow-up period (as continuous variables) correlated with the incidence of hypertension. Furthermore, both the yearly increase in sodium intake and baseline sodium intake showed significant correlations with the yearly increase in systolic blood pressure in multivariate regression analysis after adjustment for possible risk factors. Conclusions Both relatively high levels of dietary sodium intake and gradual increases in dietary sodium are associated with future increases in blood pressure and the incidence of hypertension in the Japanese general population.

INTRODUCTION:We have reported that the circadian rhythm of urinary potassium excretion (U(K)V) is determined by the rhythm of urinary sodium excretion (U(Na)V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U(Na)V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U(K)V during ARB treatment has not been reported.MATERIALS AND METHODS:Circadian rhythms of U(Na)V and U(K)V were examined in 44 patients with CKD undergoing treatment with ARB.RESULTS:Whole-day U(Na)V was not altered by ARB whereas whole-day U(K)V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U(Na)V and U(K)V (r=0.56, p<0.0001). Whole-day U(K)V/U(Na)V ratio (p=0.0007) and trans-tubular potassium concentration gradient (p=0.002) were attenuated but their night/day ratios remained unchanged. The change in the night/day U(K)V ratio correlated directly with the change in night/day U(Na)V ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance.CONCLUSIONS:The circadian rhythm of U(K)V was determined by the rhythm of UNaV even during ARB treatment. Changes in the circadian U(K)V rhythm were not determined by aldosterone but by U(Na)V.

Kidney function and cardiovascular disease are closely connected and albuminuria is a proven marker of cardiovascular risk. The present study investigated the prevalence and characteristics of albuminuria in patients with hypertension. Outpatients with essential hypertension under medical treatment were enrolled in this study (n = 350, 70.0 ± 11.4 years old). Urine samples were collected for the measurement of albumin concentration, which are expressed as the ratio of urine albumin to creatinine concentration (mg/g Cr). Cross-sectional analyses were also performed of the relationships between urinary albumin and other variables. Urinary albumin was detected in 88.3% of patients, while only 35.4% showed abnormal albuminuria (≥30 mg/g Cr). The presence of abnormal albuminuria was independently correlated with systolic blood pressure, B-type natriuretic peptide and C-reactive protein by multivariate analysis (P < 0.05). Furthermore, multivariate regression analysis identified systolic blood pressure, serum creatinine, B-type natriuretic peptide and C-reactive protein as the only factors showing independent correlation with urinary albumin (P < 0.05). Thus, approximately 35% of hypertensive patients had abnormal albuminuria. Urinary albumin was closely associated with blood pressure, C-reactive protein and B-type natriuretic peptide, indicating that the severity of albuminuria parallels that of systemic inflammation, cardiac load and blood pressure.

WRITING COMMITTEE Katsuyuki ANDO (University of Tokyo) Toshihiko ISHIMITSU (Dokkyo Medical University) Sadayoshi ITO (Tohoku University) Masaaki ITO (Mie University) Hiroshi ITOH (Keio University) Yutaka IMAI (Tohoku University) Tsutomu IMAIZUMI (Kurume University) Hiroshi IWAO (Osaka City University) Shinichiro UEDA (University of the Ryukyus) Makoto UCHIYAMA (Uonuma Kikan Hospital) Satoshi UMEMURA (Yokohama City University) Yusuke OHYA (University of the Ryukyus) Katsuhiko KOHARA (Ehime University) Hisashi KAI (Kurume University) Naoki KASHIHARA (Kawasaki Medical School) Kazuomi KARIO (Jichi Medical University) Yuhei KAWANO (National Cardiovascular Center) Genjiro KIMURA (Nagoya City University) Hiroo KUMAGAI (National Defense Medical College) Issei KOMURO (University of Tokyo) Ikuo SAITO (Keio University) Shigeyuki SAITOH (Sapporo Medical University) Kazuyuki SHIMADA (Jichi Medical University) Kazuaki SHIMAMOTO (Sapporo Medical University) Tatsuo SHIMOSAWA (University of Tokyo) Hiromichi SUZUKI (Saitama Medical University) Norio TANAHASHI (Saitama Medical University) Kouichi TAMURA (Yokohama City University) Takuya TSUCHIHASHI (Steel Memorial Yahata Hospital) Mitsuhide NARUSE (NHO Kyoto Medical Center) Koichi NODE (Saga University) Jitsuo HIGAKI (Ehime University) Naoyuki HASEBE (Asahikawa Medical College) Toshiro FUJITA (University of Tokyo) Masatsugu HORIUCHI (Ehime University) Hideo MATSUURA (Saiseikai Kure Hospital) Katsuyuki MIURA (Shiga University of Medical Science) Shokei KIM-MITSUYAMA (Kumamoto University) Ryuichi MORISHITA (Osaka University) Hiromi RAKUGI (Osaka University)

Correction to: Hypertension Research (2009) 32, 3–107; doi:10.1038/hr.2008.15, doi:10.1038/hr.2008.10, doi:10.1038/hr.2008.11 In response to the interim report on the Shiga Microalbuminuria Reduction Trial (SMART study), the Japanese Society of Hypertension (JSH) hereby announces revisions to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH2009).

Central blood pressure may be more closely associated with cardiovascular events than peripheral blood pressure. The aim of the present study was to investigate central blood pressure responses to exercise. Apparently healthy 18 subjects were enrolled in the study (38 ± 6 years) and changes in central and brachial blood pressure were recorded in response to ergometer and hand-grip exercises. Central blood pressure was estimated using an automated device (Omron HEM-9000AI). Systolic brachial blood pressure was increased after both ergometer (from 119 ± 10 to 172 ± 16 mmHg; P < 0.001) and hand-grip (from 118 ± 8 to 122 ± 9 mmHg; P = 0.001) exercises, but central systolic blood pressure was increased only after hand-grip exercise (from 117 ± 11 to 121 ± 12 mmHg; P = 0.002). The radial augmentation index was increased after hand-grip exercise, whereas ergometer exercise reduced this index. Heart rate was increased only after ergometer exercise. Thus, isometric, but not isotonic, exercise may increase central blood pressure in overall healthy subjects. The response of central blood pressure, which is a better index of cardiac load than peripheral blood pressure, to hand-grip exercise may be useful in evaluating cardiovascular risk.

Hypopotassemia with acid-base imbalance caused by laxative abuse is one of the disorders that nephrologists can be consulted for. Although laxatives are not supposed to form psychological dependence in themselves and their abuse should be cured theoretically by just finishing the overdose, the patients often resist treatment due to unpleasant symptoms such as edema and worsening constipation. Thus, chronic laxative abuse is often regarded as a drug addiction. We report a successfully treated case of chronic laxative abuse, where drastic reduction of laxatives was achieved by applying diuretics. After drastic reduction of laxatives, diuretics were added until they eased edema and bloating so that the patient could feel them to be tolerable, paying attention to lab data such as potassium and renal function. The diuretics, which substituted for laxatives in fluid control, could be tapered off over 3 months without any withdrawal symptoms or a need of additional laxatives. Our experience of simple but successful treatment of chronic laxative abuse emphasizes importance of physical management and suggests that there are cases where the two different kinds of drugs, laxatives and diuretics, can practically be regarded as swappable in the treatment of laxative abuse. This presentation should contribute to accumulation of knowledge in how to treat chronic laxative abuse where no standardized method is established yet.

Objectives: Microalbuminuria is closely associated with an increased risk of renal and cardiovascular adverse outcomes. The present study tested the hypothesis that titration of telmisartan reduces urinary excretion of albumin more than does addition of amlodipine in patients treated with a standard dose of telmisartan combined with a low-dose diuretic for the same degree of blood pressure (BP) reduction.Methods: Hypertensive patients with type 2 diabetes mellitus and microalbuminuria under treatment with a combination of a standard dose of telmisartan (40 mg/day) and trichlormethiazide (1 mg/day) were randomly assigned to receive either an increased dose of telmisartan (80 mg/day) combined with trichlormethiazide [increased dose angiotensin receptor blocker (ARB) group, n = 20] or a combination consisting of telmisartan (40 mg/day), trichlormethiazide, and amlodipine (5 mg/day) (triple combination group, n 20) for 6 months. The primary endpoint was a reduction in urinary albumin levels.Results: Although BP was reduced to a similar extent by the two regimens, patients receiving the increased dose ARB showed a higher reduction in urinary albumin (-37.4 +/- 16.9%) than those on the triple combination regimen (-8.9 +/- 23.7%; P < 0.0001). The reduction in urinary albumin was correlated with the drop in BP in the latter group, but not in the increased dose ARB group.Conclusion: Uptitration of telmisartan more effectively reduces urinary albumin than addition of amlodipine in hypertensive patients with diabetes treated with a combination of telmisartan and diuretic for the same degree of BP reduction.

BackgroundThis study sought to evaluate the prevalence of coronary artery disease (CAD) and the impact of epicardial fat volume (EFV) on CAD in symptomatic patients with a zero calcium score (CS) using multislice computed tomography (MSCT).MethodsIn this study, 1308 consecutive symptomatic patients who underwent 64-slice MSCT with a zero CS were evaluated. EFV was quantified with CS data sets. Presence of an obstructive plaque (diameter stenosis >50%) and a CT-derived vulnerable plaque, which was defined as a plaque with remodeling index >1.10 and mean CT density value <30HU, was assessed with a CT coronary angiography.ResultsObstructive plaques were detected in 86 patients (7%) and CT-derived vulnerable plaques in 63 (5%). EFV was larger in patients with obstructive plaques than no plaque (124.3±43.2cm3 vs. 95.1±40.3cm3; p<0.01). Patients with CT-derived vulnerable plaques had a greater amount of EFV than no plaque (133.0±40.2cm3 vs. 95.1±40.3cm3; p<0.01). Multivariate analysis revealed EFV as a predictor of the presence of an obstructive and a CT-derived vulnerable plaque (per 10cm3; Odds ratio (OR) 1.10; 95% confidence interval (CI), 1.04-1.16; p<0.01 and OR 1.19; 95% CI, 1.12-1.27; p<0.01). The combination of EFV and Framingham risk score (FRS) resulted in an area under the receiver-operating characteristic curve for prediction of obstructive and CT-derived vulnerable plaque of 0.75 and 0.75, which was significantly higher than 0.68 and 0.64 for FRS alone (p=0.02 and p<0.01).ConclusionsA zero CS doesn't exclude CAD and EFV can be a useful marker of CAD in symptomatic zero CS patients.