Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis.

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.

Increased double product on Monday morning during work.

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.

Effects of atorvastatin on renal function in patients with dyslipidemia and chronic kidney disease: assessment of clinical usefulness in CKD patients with atorvastatin (ASUCA) trial.

BACKGROUND: Dyslipidemia is a risk factor for the progression of chronic kidney disease (CKD). While conventional lipid lowering therapy provides a benefit to CKD management, the effect of statins on eGFR remains unclear. METHODS: A prospective, multi-center, open-labeled, randomized trial. Total of 349 CKD patients with hyperlipidemia were randomized into 2 groups, and followed for 2 years. Group A included patients who were treated with atorvastatin. Group C were treated with conventional lipid lowering drugs other than statin. Primary endpoint was changes in eGFR. Secondary endpoints included changes in urinary albumin excretion, serum LDL-C, serum triglyceride, cardio-vascular events and all-cause mortality. RESULTS: As the primary endpoint, eGFR decreased by 2.3 ml/min/1.73 m2 in Group A and by 2.6 ml/min/1.73 m2 in Group C, indicating that there was no difference in change of eGFR between the two groups. As secondary endpoints, atorvastatin succeeded to reduce serum LDL-C level significantly and rapidly, but conventional therapy did not. In fact, mean LDL-C level did not reach the target level of 100 mg/dl in Group C. Serum triglyceride was lowered only by atorvastatin, but not conventional drugs. The number of cardiovascular events and all-cause mortality did not differ between in two groups. CONCLUSION: The ASUCA (Assessment of Clinical Usefulness in CKD Patients with Atorvastatin) trial demonstrated that atorvastatin failed to exhibit reno-protections compared to conventional therapy in Japanese patients with dyslipidemia and CKD. It would be due in part to the ability of atorvastatin to more potently reduce serum LDL and triglycerides compared to conventional therapy.

Diuretic Action of Sodium-Glucose Cotransporter 2 Inhibitors and Its Importance in the Management of Heart Failure.

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 ß-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).

Significance of adjusting salt intake by body weight in the evaluation of dietary salt and blood pressure.

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.

Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis.

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.

Dietary Sodium Consumption Predicts Future Blood Pressure and Incident Hypertension in the Japanese Normotensive General Population.

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.

[Nocturnal hypertension and cardio-renal association].

Circadian rhythm of blood pressure (BP) is closely linked with sodium balance. With positive sodium balance the nocturnal BP is elevated, resulting in non-dipper pattern. Nocturnal BP elevation plays an important role in the cardio-renal association to cause the cardiovascular events. It is vey important, therefore, how to lower nocturnal hypertension especially in CKD.

Differential response of central blood pressure to isometric and isotonic exercises.

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.

The prevalence, characteristics, and clinical significance of abnormal albuminuria in patients with hypertension.

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.

Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker.

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.

Diuretics-assisted treatment of chronic laxative abuse.

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.

The prevalence and characteristics of microalbuminuria in the general population: a cross-sectional study.

BACKGROUND: Microalbuminuria is a marker of cardiovascular events. This study investigated the prevalence of microalbuminuria in the general population and the factors that can affect urinary excretion of albumin. METHODS: Apparently healthy subjects who participated in a health checkup at our hospital were enrolled in this study (n = 7963, male 64.0%, 56.2 ± 11.8 years old) Urine samples were collected for the measurement of albumin concentrations, which were expressed as the ratio of urinary albumin to creatinine concentrations (UACR [mg/g Cr]). Individual salt intake was assessed by estimating the 24-hour urinary salt excretion of subjects. RESULTS: The mean blood pressure was 124 ± 15/76 ± 10 mmHg and 31.6%, 7.4%, and 44.1% of subjects had hypertension, diabetes mellitus, and dyslipidemia, respectively. Urinary albumin was detected in 7265 subjects (91.2%: UACR ≥ 300 mg/g Cr, 0.5%; 300 > UACR ≥ 30 mg/g Cr, 4.6%; 30 > UACR ≥ 20 mg/g Cr, 2.4%; 20 > UACR ≥ 10 mg/g Cr, 8.7%; 10 > UACR ≥ 5 mg/g Cr, 21.8%; UACR < 5 mg/g Cr, 53.2%). In subjects with detectable albuminuria, UACR was independently correlated with age, systolic blood pressure, serum creatinine, fasting plasma glucose, and salt intake after adjustment for possible factors (P < 0.0001). CONCLUSION: The prevalence of microalbuminuria was found to be 4.6% in the general population. The urinary excretion of albumin was closely associated with blood pressure and salt intake. These data indicated the importance of salt restriction for the prevention of cardiovascular disease and end-stage renal disease.

Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure.

OBJECTIVE: The sympathetic nervous system plays an important role in blood pressure regulation even in the early stages of chronic kidney disease (CKD). METHODS: To understand the role of the sympathetic system, we examined the relationship between day/night ratios of both heart rate (HR) and mean arterial pressure (MAP) as well as HR variability (HRV, SD) before and during an 8-week treatment with the angiotensin II receptor blocker (ARB), olmesartan, in 45 patients with CKD. RESULTS: The day/night HR ratio strongly correlated with the day/night MAP ratio before and during ARB treatment. The ratio of [day/night HR ratio] over [day/night MAP ratio] was increased as renal function deteriorated at baseline (r = -0.31, P = 0.04), and it was attenuated (1.10 ±â€Š0.10 to 1.06 ±â€Š0.10; P = 0.04) and became independent of renal function during ARB treatment (r = -0.04, P = 0.8). ARB increased both the day/night HR ratio (1.17 ±â€Š0.09 to 1.21 ±â€Š0.13; P = 0.04) and HRV (10.6 ±â€Š2.9 to 11.7 ±â€Š4.2; P = 0.04), which were lower when baseline renal function deteriorated. CONCLUSION: The present study indicates that there exists a close correlation in circadian rhythms between HR and MAP in CKD. Synchronization between the two rhythms was progressively lost as renal function deteriorated, and ARB partly restored the synchronization. These findings suggest that the sympathetic nervous system is activated as renal function deteriorates, and ARB may suppress its activation.