Significance of blood pressure variability in normotensive individuals as a risk factor of developing hypertension.

PURPOSE: Visit-to-visit blood pressure variability is a strong predictor of the incidence of cardiovascular events and target organ damage due to hypertension. The present study investigated whether year-to-year blood pressure variability predicts the risk of hypertension in the Japanese general population. MATERIALS AND METHODS: This study analysed 2806 normotensive individuals who participated in our physical check-up program for five years in a row from 2008 to 2013. The average, standard deviation, coefficient of variation, average real variability, and highest value of systolic blood pressure in the five consecutive visits were determined and used as baseline data. The participants were followed up for the next 6 years with the development of 'high blood pressure', an average blood pressure level of ≥140/90 mmHg or the use of antihypertensive medications, as the endpoint. RESULT: During follow-up, 'high blood pressure' developed in 389 participants (13.9%, 29.5 per 1 000 person-years). The incidence increased across the quartiles of standard deviation and average real variability, while the average and highest systolic blood pressure had the most prominent impact on the development of 'high blood pressure'. Multivariate logistic regression analysis adjusted for possible risk factors indicated that the average, standard deviation, average real variability, and highest blood pressure, but not the coefficient of variation of systolic blood pressure, were significant predictors of 'high blood pressure'. CONCLUSION: Increased year-to-year blood pressure variability predicts the risk of hypertension in the general normotensive population. The highest blood pressure in the preceding years may also be a strong predictor of the risk of hypertension.

What is the context A relatively high blood pressure level recorded by chance is not usually examined further, especially in cases where the blood pressure values recorded in different opportunities were within normal levels.However, high blood pressure observed by chance may be a result of increased blood pressure variability.Increased blood pressure variability predicts incident hypertension in patients with diabetes, but clinical significance of increased blood pressure variability in the general population with normal blood pressure has not been studied.What is new The impact of blood pressure variability on the development of hypertension in the normotensive general population was investigated.The present study demonstrated that increased blood pressure variability was the significant predictor of the development of hypertension in the general population.What is the impact Increased year-to-year blood pressure variability as well as the highest blood pressure observed by chance in the preceding years is a strong predictor of the development of hypertension in the general normotensive population.

Excessive salt intake reduces bone density in the general female population.

BACKGROUND: Osteoporosis is a multifactorial disorder in which nutrition is associated with its onset and progression. Excessive salt intake is closely associated with the onset and progression of various diseases, such as osteoporosis and hypertension. We investigated the effects of dietary salt intake on bone density in the general female population. METHODS: In 884 female participants (60.1 ± 10.1 years old) who visited our hospital for an annual physical checkup, salt intake (g/day) was assessed using a spot urine sample, and bone density was evaluated as a speed of sound (m/s) of ultrasonic pulses in a calcaneus by quantitative ultrasound. We investigated the relationship between bone density and salt intake and the differences in bone density or salt intake between the presence and absence of lifestyle-related diseases such as hypertension, diabetes mellitus and dyslipidaemia. RESULTS: The average bone density and salt intake were 1497 ± 26 m/s and 8.5 ± 1.8 g/day, respectively. Univariate and multivariate regression analyses revealed that bone density was significantly negatively associated with salt intake. Bone density was lower, and salt intake was higher in participants with hypertension, diabetes mellitus and dyslipidaemia than in those without. After adjusting for age, hypertension, diabetes mellitus and dyslipidaemia, bone density was negatively correlated with salt intake. CONCLUSIONS: We confirmed that excessive salt intake reduces bone density independently of age and lifestyle-related diseases in the general female population. Since dietary salt intake is a modifiable factor, osteoporosis can be prevented by dietary intervention, including salt reduction.

Current status and recent changes in blood pressure and dietary salt consumption in Japanese individuals.

Purpose: Treatment of hypertension has recently shown remarkable advances. It is quite important to survey the current general status of blood pressure (BP) and recent changes to verify whether people are benefitting from these advances. The present study aimed to investigate the current status of, and recent changes in, BP, the prevalence and treatment rate of hypertension, the achievement rate of target BP, and salt intake in Japanese individuals. Methods: Recent changes in salt intake as well as BP, the prevalence and treatment rate of hypertension, and the rate of achievement of target BP were investigated in participants in our yearly physical checkup program from 2009 to 2018 (n = 79,789). Individual salt intake was assessed by estimating 24-hour urinary sodium excretion using a spot urine sample. Results: The prevalence of hypertension did not change, but the treatment rate of hypertension (from 64% to 75%) and the achievement rate of the target BP improved during the period (from 35% to 57%). BP decreased, prominently in hypertensive participants under antihypertensive treatment (from 133 ± 14/84 ± 9 to 128 ± 13/76 ± 10 mmHg). Salt intake did not decline noticeably during the 10 years of observation. Conclusions: The prevalence of hypertension did not change, but the treatment rate of hypertension and the achievement rate of the target BP improved during a recent 10-year period. These findings suggest that improved pharmacological management of hypertension resulted in a gradual reduction in BP levels, but lifestyle modification has not yet really taken root in the Japanese general population.

Influence of thyroid dysfunction on brain natriuretic peptide level in health examination participants.

The tissue-specific circulating markers of thyroid hormone action on cardiac function have not been established. Although the relationship between thyroid function and plasma brain natriuretic peptide (BNP) levels has been evaluated in patients with thyroid disorders, the relationship between these parameters in the general population has not been yet studied. We conducted retrospective cohort study by health examination with concurrent measurements of TSH, free T4, body mass index, systolic blood pressure, hemoglobin, and estimated glomerular filtration rate from participants who visited the Department of Health Checkup, Enshu Hospital between July 2008 and March 2017. After participants with abnormal electrocardiogram and/or any history of cardiac disease were excluded, 2,807 individuals were subjected. Multivariate analyses demonstrated that, when compared to euthyroidism (n = 2,629), the increase in BNP levels was significant in overt thyrotoxicosis (n = 21) but not in subclinical thyrotoxicosis (n = 53) or subclinical hypothyroidism (n = 97). Interestingly, the standardized partial regression coefficient was the smallest for thyroid function category (overt thyrotoxicosis compared to euthyroidisim; ß = 0.048, p = 0.006) among the independent variables including age, body mass index, systolic blood pressure, and hemoglobin. In longitudinal comparison, we identified 986 participants who had sequential data on the measurements and were stable as euthyroidism and subclinical hypothyroidism. Their annual percent change in BNP demonstrated no significant differences. In conclusion, a direct stimulatory effect of thyroid hormone on the secretion (or production) of BNP was confirmed even in a large number of health examination participants.

Home blood pressure on winter mornings could be exaggerated: A comparison with summer mornings.

PURPOSE: Self-measured blood pressure at home (HBP) is quite important for the management of hypertension. We hypothesized that winter HBP measured according to the recommendation of the guidelines, but not HBP measured inside bed before getting up, is elevated in response to cold ambient temperatures in winter. This study aimed to investigate differences in HBP measured before and after getting up in winter and summer.Methods: Hypertensive subjects whose blood pressure was stably controlled were enrolled (n = 46, 73 years). They were instructed to measure HBP while in bed just after waking (HBP-bed), in addition to the ordinary HBP measurement in the morning (HBP-morning) according to the guidelines. The mean value of HBP for 7 consecutive days before the day of a regular hospital visit was considered as the HBP of each subject, and characteristics of the winter and summer BPs were investigated.Results: HBP-morning was significantly higher (P < .001) in winter than in summer, but HBP-bed was lower in winter than in summer (P < .05). HBP-morning was significantly higher than HBP-bed in winter, while HBP-morning was not different from HBP-bed in summer, resulting in greater changes in HBP after getting up in winter than in summer (P < .0001). Changes in HBP after getting up were significantly correlated with serum creatinine levels and the urinary albumin-to-creatinine ratio.Conclusions: These findings imply that elevated HBP-morning in winter reflects the response of BP to cold after getting up. Seasonal profiles of HBPs before and after getting up should be noted in the management of hypertension.

Plasma Globotriaosylsphingosine Level as a Primary Screening Target for Fabry Disease in Patients With Left Ventricular Hypertrophy.

BACKGROUND: Although previous studies have suggested a certain prevalence of Fabry disease (FD) in left ventricular hypertrophy (LVH) patients, the screening of FD is difficult because of its wide-ranging clinical phenotypes. We aimed to clarify the utility of combined measurement of plasma globotriaosylsphingosine (lyso-Gb3) concentration and α-galactosidase A activity (α-GAL) as a primary screening of FD in unexplained LVH patients.Methods and Results:Between 2014 and 2016, both lyso-Gb3 and α-GAL were measured in 277 consecutive patients (male 215, female 62, age 25-79 years) with left ventricular wall thickness >12 mm on echocardiogram: 5 patients (1.8%) screened positive (2 (0.7%) showed high lyso-Gb3 and 4 (1.4%) had low α-GAL levels). Finally, 2 patients (0.7%) were diagnosed with clinically significant FD. In 1 case, a female heterozygote with normal α-GAL levels had genetic variants of unknown significance and was diagnosed as FD by endomyocardial biopsy. The other case was a male chronic renal failure patient requiring hemodialysis, and he had a p.R112H mutation. In both cases there were high lyso-Gb3 levels. CONCLUSIONS: The serum lyso-Gb3 level can be relevant for clinically significant FD, and combined measurement of lyso-Gb3 and α-GAL can provide better screening of FD in unexplained LVH patients.

Factors associated with longitudinal changes in serum concentrations of Mac-2 binding protein: A prospective 3-year observational study.

BACKGROUND AND AIMS: Mac-2 binding protein (M2BP) plays an important role in cell adhesion. In a recent cross-sectional study we reported that serum M2BP concentrations may reflect silent atherosclerosis. The aim of the present prospective follow-up study was to investigate possible relationships between changes in concentrations of M2BP and other factors over a >3-year period. METHODS AND RESULTS: The present study enrolled subjects who visited Enshu hospital from 2014 to 2015 for a periodic physical check-up and then attended for another physical check-up after >3 years (n = 174). Factors affecting changes in M2BP concentrations were investigated at both baseline and follow-up. Subjects with liver dysfunction, a history of hepatic disease, malignant neoplasm, or cardiovascular events at baseline were excluded. Univariate and multivariate regression analyses showed that changes in serum M2BP concentrations during the follow-up period were significantly associated with changes in low-density lipoprotein cholesterol (LDL-C), triglyceride, and oxidative stress marker derivatives of reactive oxygen metabolites (d-ROM) concentrations. Moreover, the increase in LDL-C was significantly greater in subjects in whom M2BP concentrations increased during the follow-up period. Logistic regression analysis with an endpoint of increased M2BP revealed that increased LDL-C was an independent determinant of an increase in M2BP during the follow-up period. CONCLUSION: During the observation period of >3 years, serum M2BP concentrations were increased in subjects who also exhibited increases in levels of metabolic parameters, especially LDL-C, and the oxidative stress marker d-ROM. These results support that serum M2BP reflects one of the contributors to the progression of silent atherosclerosis.

Dietary Salt Intake is a Significant Determinant of Impaired Kidney Function in the General Population.

BACKGROUND/AIMS: Kidney dysfunction is an important risk factor for cardiovascular disease and end-stage renal disease. This study investigated whether dietary salt intake predicts deterioration of kidney function in the general population. METHODS: In all, 12 126 subjects with a normal estimated glomerular filtration rate (eGFR ≥60 mL/min per 1.73m2) attending an annual check-up were enrolled in the study and were followed-up for a median of 1754 days; the endpoint was the development of impaired kidney function (eGFR < 60 mL/min per 1.73m2). Individual salt intake was estimated using spot urine analysis. RESULTS: At baseline, mean (± SD) salt intake and eGFR were 10.6 ± 3.4 g/day and 80.8 ± 12.9 mL/min per 1.73m2, respectively. During the follow-up period, 1384 subjects (25.2 per 1000 person-years) developed impaired kidney function. Multivariate Cox hazard regression analysis revealed salt intake as a significant predictor of the new onset of kidney impairment (hazard ratio 1.045; 95% confidence interval 1.025-1.065). Subjects were divided into two groups based on salt intake; the incidence of impaired kidney function was higher in the group with high than low salt intake (P < 0.001, log-rank test). Multivariate Cox hazard regression analysis indicated a 29% increased risk of developing impaired kidney function in the high-salt group. Multivariate linear regression analysis showed a significant correlation between salt intake and yearly decline in eGFR (ß = 0.060, P < 0.001). CONCLUSION: Salt intake is associated with the development of impaired kidney function in the general population, independent of its effects on blood pressure. Salt restriction may help prevent the development of impaired kidney function.

Does Treatment of Impaired Glucose Tolerance Improve Cardiovascular Outcomes in Patients with Previous Myocardial Infarction?

PURPOSE: We evaluated the effects of an alpha-glucosidase inhibitor, voglibose, on cardiovascular events in patients with a previous myocardial infarction (MI) and impaired glucose tolerance (IGT). METHODS: This prospective, randomized, open, blinded-endpoint study was conducted in 112 hospitals and clinics in Japan in 3000 subjects with both previous MI and IGT receiving voglibose (0.6 mg/day, n = 424) or no drugs (n = 435) for 2 years. The Data and Safety Monitoring Board (DSMB) recommended discontinuation of the study in June 2012 after an interim analysis when the outcomes of 859 subjects were obtained. The primary endpoint was cardiovascular events including cardiovascular death, nonfatal MI, nonfatal unstable angina, nonfatal stroke, and percutaneous coronary intervention/coronary artery bypass graft. Secondary endpoints included individual components of the primary endpoint in addition to all-cause mortality and hospitalization due to heart failure. RESULTS: The age, ratio of males, and HbA1C were 65 vs. 65 years, 86 vs. 87%, and 5.6 vs. 5.5% in the groups with and without voglibose, respectively. Voglibose improved IGT; however, Kaplan-Meier analysis showed no significant between-group difference with respect to cardiovascular events [12.5% with voglibose vs. 10.1% without voglibose for the primary endpoint (95% confidence interval, 0.82-1.86)]; there were no significant differences in secondary endpoints. CONCLUSION: Although voglibose effectively treated IGT, no additional benefits for cardiovascular events in patients with previous MI and IGT were observed. Voglibose may not be a contributing therapy to the secondary prevention in patients with MI and IGT. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT00212017.

Does N-terminal Pro-brain Type Natriuretic Peptide Predict Cardiac Complications After Hip Fracture Surgery?

BACKGROUND: Elderly patients with hip fracture are at risk for cardiac complications. N-terminal pro-brain type natriuretic peptide (NT-proBNP) has been shown to predict cardiac complications in surgical patients; however, to our knowledge, only two studies have evaluated the utility of this test in patients with hip fracture. We believe it is important to assess a more accurate cutoff value of NT-proBNP with exclusion of patients with renal failure. QUESTIONS/PURPOSES: To assess the association between preoperative NT-proBNP and cardiac complications after hip fracture surgery. METHODS: We performed 450 surgical procedures in patients with hip fractures between January 2011 and December 2014. Exclusion criteria were renal dysfunction and inadequate laboratory tests. The final study population consisted of 328 patients (mean age, 83 years; 80% women). Preoperatively, measurement of NT-proBNP level was performed. The primary endpoint was the occurrence of cardiac complications within 14 days after surgery based on a chart review. The predictive value of NT-proBNP was assessed using multivariate logistic regression analysis, controlling for relevant confounding variables such as age, gender, body weight, and renal function; we also performed receiver operating characteristic (ROC) curve analysis. Postoperative cardiac complications were encountered in 7% of patients (24 of 328). RESULTS: The median preoperative NT-proBNP level was higher in patients with complications than in those without (1090 [interquartile range, 614-3191 pg/mL] vs 283 pg/mL [interquartile range, 137-507 pg/mL], p < 0.001). The cutoff level of NT-proBNP determined by ROC curve analysis was 600 pg/mL, with a sensitivity, specificity, positive predictive value, and negative predictive value of 79%, 81%, 25%, and 98%, respectively, and the area under the ROC curve was 0.87 (95% CI, 0.80-0.94; p < 0.001). After controlling for potentially relevant confounding variables, we found a preoperative NT-proBNP greater than 600 pg/mL was associated with an increased risk of cardiac complications (odds ratio, 13; 95% CI, 4-38; p < 0.001) compared with those with NT-proBNP less than 600 pg/mL. CONCLUSIONS: Preoperative NT-proBNP greater than 600 pg/mL is independently associated with postoperative cardiac complications in patients with hip fracture without renal dysfunction. NT-proBNP measurement provides additional information and is clinically useful for predicting cardiac complications during the early phase after hip fracture surgery. Future studies might develop a simple index for prediction of postoperative cardiac complication including cutoff values of NT-proBNP. LEVEL OF EVIDENCE: Level III, diagnostic study.

Kidney function crucially affects B-type natriuretic peptide (BNP), N-terminal proBNP and their relationship.

BACKGROUND: B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are useful biomarkers in the management of heart failure. Both peptides are secreted into the circulation after cleavage of their precursor proBNP and excreted from the kidney in the active form or as metabolites. We investigated effects of kidney function on the levels and association of these peptides. MATERIALS AND METHODS: Plasma concentrations of BNP and serum concentrations of NT-proBNP were measured in 229 outpatients of our cardiology department (male/female = 138/91, mean age= 68 years) and 53 hospital outpatients on chronic haemodialysis (30/23, 68 years). Kidney function in nondialysed patients was assessed by estimated glomerular filtration rate (eGFR; mL/min/1.73 m(2)) and categorised across five stages. Effects of kidney function on BNP, NT-proBNP and their relationship were investigated. RESULTS: Deterioration in kidney function increased BNP and NT-proBNP levels, as well as the NT-proBNP/BNP ratio, and these values were highest in patients on haemodialysis. The eGFR inversely correlated with BNP (r = -0.472), NT-proBNP (r = -0.579), and the NT-proBNP/BNP ratio (r = -0.454, all P < 0.0001). A significant correlation was observed between BNP and NT-proBNP at all stages of kidney function including patients on haemodialysis, but the correlation was significantly affected by kidney function. CONCLUSIONS: Although circulating levels of both BNP and NT-proBNP increased with deteriorating kidney function, the impact of kidney function on NT-proBNP was much more pronounced than that on BNP. Kidney function should be taken into account when interpreting data on BNP, NT-proBNP and their relationship.

Central blood pressure reflects left ventricular load, while brachial blood pressure reflects arterial damage.

OBJECTIVES: The present study investigated whether brachial and central blood pressures have differential impact on the cardiovascular system in the general population. METHODS: The study included 706 subjects (59 ± 10 years) who visited our hospital for a physical check-up. Brachial blood pressure and radial artery pressure waveforms were recorded using an automated device, and the pressure corresponding to the radial late systolic peak (SBP2) was taken as central blood pressure. The concentration of B-type natriuretic peptide and the intima-media thickness of the carotid artery were measured and a cross-sectional analysis was performed. RESULTS: Brachial blood pressure was 128 ± 18/74 ± 12 (mean blood pressure, 92 ± 13) mmHg and SBP2 was 120 ± 19 mmHg. Although both brachial systolic blood pressure and SBP2 correlated with B-type natriuretic peptide in a univariate analysis, only SBP2 independently correlated with B-type natriuretic peptide after adjustment for possible factors. In contrast, brachial systolic blood pressure, but not SBP2, independently correlated with carotid artery intima-media thickness. CONCLUSIONS: Central blood pressure is more closely associated with left ventricular load than brachial blood pressure, while brachial blood pressure is more strongly associated with vascular damage than central blood pressure.

Urinary Na/K ratio is a predictor of developing chronic kidney disease in the general population.

Chronic kidney disease (CKD) is a major risk factor for cardiovascular diseases as well as end-stage kidney disease. Increased dietary sodium (Na) or decreased dietary potassium (K) deteriorates kidney function; however, findings regarding the association of dietary Na/K ratio with kidney function are limited and conflicting. Therefore, the present study investigated the impact of urinary Na/K ratio on the development of CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, in the Japanese general population. In total, 14,549 subjects without CKD who participated in our medical checkup were enrolled. The urinary Na/K ratio was measured using a sample of overnight urine. The subjects were followed up until the endpoint (onset of CKD). During the median follow-up period of 61.4 months, CKD developed in 2096 participants (25.9 per 1000 person-years). The risk of developing CKD increased across the quartiles of baseline urinary Na/K ratio in the Kaplan-Meier analysis (log-rank, P < 0.001). In multivariate Cox proportional hazard regression analysis, urinary Na/K ratio was a significant predictor of new-onset CKD after adjustment for important factors including eGFR at baseline (hazard ratio, 2.013; 95% confidence interval, 1.658-2.445; p < 0.001). Moreover, baseline urinary Na/K ratio was found to be independently correlated with yearly decline in eGFR. Similar results were obtained in subgroups of participants with and without hypertension. Thus, urinary Na/K ratio is significantly associated with the development of CKD in the general population.

Impact of medical checkup parameters on major adverse cardiovascular events in the general Japanese population.

Medical checkups play a role in the identification of individuals at increased cardiovascular risk. However, the impact of each medical examination parameter on the incidence of major adverse cardiovascular events (MACE) has not been intensively studied. Here we assessed the predictors of MACE among parameters examined during medical checkups in the general Japanese population. A total of 13,522 individuals (mean age, 52.8 ± 12.3 years) who participated in our medical checkup program from 2008 to 2015 were followed up for a median of 1,827 days with the endpoint of MACE. MACE included cardiovascular death, non-fatal myocardial infarction, angina, decompensated heart failure, stroke, and other cardiovascular events requiring hospitalization. Possible associations between MACE and baseline clinical test parameters were investigated. During follow-up, MACE occurred in 196 participants. Participants with hypertension, diabetes mellitus, dyslipidemia, or metabolic syndrome were at increased risk of MACE on the univariate analysis. Multivariate Cox hazard analysis demonstrated that male sex, age, systolic blood pressure, and baseline B-type natriuretic peptide level were independently correlated with future MACE after the adjustment for confounders; the impact of B-type natriuretic peptide was most prominent among the investigated variables. These results suggest that B-type natriuretic peptide level obtained during a medical checkup examination is an independent and strong predictor of MACE. The inclusion of BNP as part of medical checkup parameters may improve the ability to identify individuals at increased cardiovascular risk and prevent cardiovascular disease among them.

Distinctive left ventricular-arterial and right ventricular-pulmonary arterial coupling observed in patients with heart failure and a higher left ventricular ejection fraction range.

AIMS: Higher left ventricular (LV) ejection fraction (EF) is related to unfavourable prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The cause of this finding needs to be haemodynamically explained. Thus, we investigated this crucial issue from the perspective of LV-arterial (A) and right ventricular (RV)-pulmonary arterial (PA) coupling. METHODS AND RESULTS: Study patients were derived from our prospective cohort study of patients hospitalized due to acute decompensated HF and LVEF > 40%. We divided the 255 patients into three groups: HF with mildly reduced EF (HFmrEF), HFpEF with 50% ≤ LVEF < 60%, and HFpEF with LVEF ≥ 60%. We compared LV end-systolic elastance (Ees), effective arterial elastance (Ea), and Ees/Ea as a representative of LV-A coupling among groups and compared the ratio of tricuspid annular plane excursion to peak pulmonary arterial systolic pressure (TAPSE/PASP) as a representative of RV-PA coupling. All-cause death and readmission due to HF-free survival was worse in the group with a higher LVEF range. Ees/Ea was greater in HFpEF patients with LVEF ≥ 60% (2.12 ± 0.57) than in those with 50% ≤ LVEF < 60% (1.20 ± 0.14) and those with HFmrEF (0.82 ± 0.09) (P < 0.001). PASP was increased in the groups with higher LVEF; however, TAPSE/PASP did not differ among groups (n = 168, P = 0.17). In a multivariate Cox proportional hazard model, TAPSE/PASP but not PASP was significantly related to event-free survival independent of LVEF. CONCLUSION: HFpEF patients with higher LVEF have unfavourable prognosis and distinctive LV-A coupling: Ees/Ea is elevated up to 2.0 or more. Impaired RV-PA coupling also worsens prognosis in such patients. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000017725.

Dietary salt intake predicts future development of metabolic syndrome in the general population.

Excessive dietary salt consumption is one of the most important risk factors for hypertension. Metabolic disorders often coexist with hypertension, and excess salt intake has been reported to underlie metabolic disorders, such as insulin resistance. Therefore, we tested the hypothesis that excessive dietary salt causes metabolic syndrome in the general population. In total, 13886 subjects who participated in our medical checkup were enrolled, and salt intake was assessed using a spot urine sample. The characteristics of participants with metabolic syndrome (n = 1630) were examined at baseline, and then participants without metabolic syndrome (n = 12256) were followed up with the endpoint being the development of metabolic syndrome. The average estimated salt intake in our participants was 8.72 ± 1.93 g/day. A significant association between salt intake and metabolic syndrome was obtained from the logistic regression analysis, and salt intake increased as the number of metabolic disorders in an individual increased at baseline (P < 0.001). During the median follow-up period of 52 months, 1669 participants developed metabolic syndrome. Kaplan-Meier analysis demonstrated an increased risk of metabolic syndrome across quartiles of baseline salt intake (log-rank, P < 0.001). In the Cox proportional hazard regression analysis where salt intake was taken as a continuous variable, salt intake at baseline was an independent predictor of developing metabolic syndrome. These results suggest that excessive salt intake is significantly associated with the development of metabolic syndrome in the general population. Salt may play an important role in the development of metabolic disorders and hypertension.

Unfavourable outcomes in patients with heart failure with higher preserved left ventricular ejection fraction.

AIMS: Newly introduced drugs for heart failure (HF) have been reported to improve the prognosis of HF with preserved ejection fraction (HFpEF) in the lower range of left ventricular ejection fraction (LVEF). We hypothesized that a higher LVEF is related to an unfavourable prognosis in patients with HFpEF. METHODS AND RESULTS: We tested this hypothesis by analysing the data from a prospective multicentre cohort study in 255 patients admitted to the hospital due to decompensated HF (LVEF > 40% at discharge). The primary endpoint of this study was a composite outcome of all-cause death and readmission due to HF, and the secondary endpoint was readmission due to HF. LVEF and the mitral E/e' ratio were measured using echocardiography. In multicovariate parametric survival time analysis, LVEF [hazard ratio (HR) = 1.046 per 1% increase, P = 0.001], concurrent atrial fibrillation (AF) (HR = 3.203, P < 0.001), and E/e' (HR = 1.083 per 1.0 increase, P < 0.001) were significantly correlated with the primary endpoint. In addition to these covariates, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use was significantly correlated with the secondary endpoint (HR = 0.451, P = 0.008). Diagnostic performance plot analysis demonstrated that the discrimination threshold value for LVEF that could identify patients prone to reaching the primary endpoint was ≥57.2%. The prevalence of AF or E/e' ratio did not differ significantly between patients with LVEF ≥ 58% and with 40% < LVEF < 58%. CONCLUSION: A higher LVEF is independently related to poor prognosis in patients with HFpEF, in addition to concurrent AF and an elevated E/e' ratio. ACEI/ARB use, in contrast, was associated with improved prognosis, especially with regard to readmission due to HF. CLINICAL TRIAL REGISTRATION: https://www.umin.ac.jp/ctr/index.htm. UNIQUE IDENTIFIER: UMIN000017725.

Falsely elevated thyroid hormone levels associated with fibrin interference in patients receiving oral anticoagulant therapy.

OBJECTIVE: Unique clinical courses were observed in two asymptomatic patients receiving warfarin who referred to our hospital because of suspected central hyperthyroidism. We eventually diagnosed these patients with falsely elevated thyroid hormone levels caused by macroscopically invisible fibrin. Although false results caused by fibrin interference in vitro have been identified in various immunoassays, especially in blood samples from patients receiving anticoagulant therapy, no studies on thyroid function testing have been reported. The experience in evaluating these cases prompted us to investigate the independent influence of oral anticoagulants via putative fibrin interference on thyroid function testing. METHODS: We retrospectively reviewed known contributing factors that affect thyroid function testing including age, gender, medication history, body mass index, estimated glomerular filtration rate, smoking status, alcohol consumption, and the seasons of hospital visits from participants who presented the Department of Health Checkup between April 2010 and December 2020. RESULTS: A propensity-matched analysis revealed that the median serum free thyroxine levels under oral anticoagulant were significantly higher (17.9 pmol/L, n = 60) than those without anticoagulants (16.0 pmol/L, n = 60; p < 0.001). It was noted that this difference was the largest among contributing factors we analyzed. No significant differences were noted in serum thyroid-stimulating hormone levels. CONCLUSIONS: We report two patients receiving warfarin with falsely elevated thyroid hormone levels caused by fibrin interference resembling central hyperthyroidism for the first time. Our retrospective study suggests that the medication status of oral anticoagulants should be considered when evaluating thyroid function tests.

Feasibility of Short-Term Aggressive Lipid-Lowering Therapy with the PCSK9 Antibody in Acute Coronary Syndrome.

BACKGROUND: The guideline-recommended low-density lipoprotein cholesterol target level of <70 mg/dL may not be achieved with statin administration in some patients with acute coronary syndrome (ACS). Therefore, the proprotein convertase subtilisin-kexin type 9 (PCSK9) antibody can be added to high-risk patients with ACS. Nevertheless, the optimal duration of PCSK9 antibody administration remains unclear. METHODS AND RESULTS: Patients were randomized to receive either 3 months of lipid lowering therapy (LLT) with the PCSK9 antibody followed by conventional LLT (with-PCSK9-antibody group) or 12 months of conventional LLT alone (without-PCSK9-antibody group). The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, unstable angina, and ischemia-driven revascularization. A total of 124 patients treated with percutaneous coronary intervention (PCI) were randomly assigned to the two groups (n = 62 in each). The primary composite outcome occurred in 9.7% and 14.5% of the patients in the with- and without-PCSK9-antibody groups, respectively (hazard ratio: 0.70; 95% confidence interval: 0.25 to 1.97; p = 0.498). The two groups showed no significant differences in hospitalization for worsening heart failure and adverse events. CONCLUSIONS: In ACS patients who underwent PCI, short-term PCSK9 antibody therapy with conventional LLT was feasible in this pilot clinical trial. Long-term follow-up in a larger scale clinical trial is warranted.

DAPagliflozin for the attenuation of albuminuria in Patients with hEaRt failure and type 2 diabetes (DAPPER study): a multicentre, randomised, open-label, parallel-group, standard treatment-controlled trial.

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the urinary albumin-to-creatinine ratio (UACR) in patients with elevated levels of albuminuria in the presence or absence of heart failure (HF) or type 2 diabetes mellitus (T2D). However, these effects have not yet been reported in the presence of both HF and T2D. This lack of evidence prompted us to conduct a clinical trial on the effects of dapagliflozin on UACR in patients with HF and T2D. Methods: DAPPER is a multicentre, randomised, open-labeled, parallel-group, standard treatment-controlled trial that enrolled patients at 18 medical facilities in Japan. Eligible participants with both HF and T2D and aged between 20 and 85 years were randomly assigned to a dapagliflozin or control (anti-diabetic drugs other than SGLT 2 inhibitors) group with a 1:1 allocation. The primary outcome was changes in UACR from baseline after a two-year observation, and secondary endpoints were cardiovascular (CV) events and parameters related to HF. This trial was registered with the UMIN-CTR registry, UMIN000025102 and the Japan Registry of Clinical Trials, jRCTs051180135. Findings: Between 12 May 2017 and 31 March 2020, 294 patients were randomly assigned to the dapagliflozin group (n = 146) or control group (n = 148). The mean age of patients was 72.1 years and 29% were female. The mean glycated hemoglobin value was 6.9%, mean NT-proBNP was 429.1 pg/mL, mean estimated GFR was 65.7 mL/min/1.73 m2, and median UACR was 25.0 (8.8-74.6) mg/g Cr in the dapagliflozin group and 25.6 (8.2-95.0) mg/g Cr in the control group. Of the 146 patients in the dapagliflozin group, 122 completed the study, and 107 (87.7%) were taking 5 mg of dapagliflozin daily at the end of the observation period. The primary outcome did not significantly differ between the dapagliflozin and control groups. Among the secondary endpoints, the mean decrease in left ventricular end-diastolic dimensions as one of the echocardiographic parameters was larger in the dapagliflozin group than in the control group. The composite endpoint, defined as CV death or hospitalisation for CV events, hospitalisation for HF events, hospitalisation for all causes, and an additional change in prescriptions for heart failure in a two-year observation, was less frequent in the dapagliflozin group than in the control group. Interpretation: Although dapagliflozin at a dose of 5 mg daily did not reduce urinary albumin excretion in patients with HF and T2D from that in the controls, our findings suggest that dapagliflozin decreased CV events and suppressed left ventricular remodeling. Funding: AstraZeneca KK, Ono Pharmaceutical Co., Ltd.