Recent studies indicate a stronger association between the urinary sodium-to-potassium (Na/K) ratio and blood pressure (BP) than individual sodium (Na) or potassium (K) levels. This study aimed to examine whether urinary Na/K ratio could predict the onset of hypertension in the general population. The ratio was calculated using overnight urine samples from 23,014 adults (mean age; 51.4 ± 13.2 years, 13,525 men) who underwent annual physical checkups between 2010 and 2023. Cross-sectional analysis of first-visit data revealed significantly higher Na/K ratios among individuals with hypertension compared to normotensive individuals (5.05 ± 2.85 vs. 4.39 ± 2.47, p < 0.001). Multiple regression analysis showed a significant association between the Na/K ratio and systolic BP. After excluding participants with hypertension, 12,483 normotensive individuals (48.7 ± 11.9 years; 7087 men) were followed for a median of 1788 days. During the follow-up period, 4056 participants developed hypertension. Kaplan-Meier analysis indicated an increased risk of hypertension across baseline Na/K ratio quartiles (log-rank, p < 0.001). Univariate Cox regression analysis identified the Na/K ratio as a significant predictor of incident hypertension, with hazard ratios increasing across quartiles. Multivariate analysis confirmed the association (hazard ratio [HR] = 1.408, 95% confidence interval [CI]; 1.225-1.619), although the Na/K ratio was not independently associated with hypertension onset after additional adjustment for baseline systolic BP. These findings suggest that the urinary Na/K ratio is significantly associated with the risk of hypertension in the general population. Therefore, dietary interventions that lower the Na/K ratio may prevent the development of hypertension.

Electrocardiogram QRS duration is associated with cardiovascular events and all-cause death. The present study was conducted to investigate the hypothesis that the QRS duration predicts the future development of hypertension in the Japanese general population with normal blood pressure. Overall, 13,382 individuals without bundle branch block, Wolff–Parkinson–White syndrome, complete atrioventricular block, pacemaker implantation, or old myocardial infarction on electrocardiogram were enrolled. The cross-sectional analysis indicated that the QRS duration was longer in hypertensive than in normotensive participants. After excluding the participants with hypertension, the remaining 9293 participants with normal blood pressure (male = 5425, 50.2 ± 11.7 years) were followed up for the median of 4 years with an endpoint of hypertension development. During the follow-up period, 1953 participants developed hypertension (50.6 per 1000 person-year). Kaplan–Meier analysis revealed that the incidence of hypertension increased across the quartiles of participants based on QRS duration at baseline as 39.0, 48.6, 53.7, and 62.4 per 1000 person-years in the first, second, third, and fourth quartiles, respectively. Univariate analysis confirmed a significant impact of QRS duration on the development of hypertension. In the multivariate Cox hazard regression analysis adjusted for possible confounding variables, QRS duration was an independent predictor of the development of hypertension. These results suggest the close association between electrocardiogram QRS duration and the future development of hypertension in the Japanese general population. Moreover, alterations in the intraventricular conduction may precede clinically apparent hypertension.

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.

Introduction: Metabolic syndrome (MetS) and chronic kidney disease are both important risk factors for cardiovascular disease and are closely related to each other. We retrospectively investigated whether MetS or its components increase the risk of development of impaired kidney function in the Japanese general population. Methods: This is a retrospective cohort study which enrolled 14,917 participants who visited our hospital for physical checkups from 2008 to 2018 and had normal estimated glomerular filtration rate (eGFR >= 60 mL/min/1.73 m(2)) during the baseline examination. Participants were followed up for the median of 1,847 days until 2019 with the development of impaired kidney function (eGFR <60 mL/min/1.73 m(2)) as the endpoint. The definition of MetS was based on Japanese diagnostic criteria (2005). Results: Throughout the study, 2,150 participants (25.9 per 1,000 person-year) developed impaired kidney function after their baseline checkup. The incidence of impaired kidney function was more frequent in participants with MetS (39.3 per 1,000 person-year) than without (24.2 per 1,000 person-year, p < 0.001). Moreover, each MetS component was positively associated with the incidence of impaired kidney function, where the incidence of impaired kidney function increased with the number of MetS components at baseline (0, 1, 2, and >= 3 component(s); 17.3, 26.9, 32.9, and 39.7 per 1,000 person-year, respectively). Multivariate Cox hazard analysis revealed that MetS was an independent risk factor for impaired kidney function after adjusting for known risk factors (hazard ratio, 1.29; 95% confidence interval, 1.15-1.45). Conclusions: Testing for MetS and its components can help evaluate the risk of developing impaired kidney function in the general population.

PurposeVisit-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 methodsThis 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.ResultDuring 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'.ConclusionIncreased 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 contextA 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 newThe 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 impactIncreased 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.

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 m 2 , 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.

The fibrosis-4 index, a noninvasive method for evaluating liver fibrosis, is closely associated with cardiovascular events. In this study, we tested the hypothesis that the fibrosis-4 index is associated with new-onset hypertension in the general population. A total of 15,502 individuals (51.0 ± 13.2 years) who participated in our health checkup program were screened. Participants with hypertension were excluded, and the remaining 8719 normotensive participants (48.4 ± 12.6 years) were followed up (median 1739 days) with the endpoint of the new onset of hypertension. During follow-up, 1750 participants (39.0 per 1000 person-years) developed hypertension. In Kaplan–Meier analysis, where participants were divided into three groups according to the fibrosis-4 index at baseline (low, <1.30; intermediate, 1.30–2.67; high, ≥2.67), the risk of hypertension increased with increasing fibrosis-4 index (low, 33.8; intermediate, 55.2; high, 69.4 per 1000 person-years). Multivariate Cox hazard regression analysis revealed that the log-transformed fibrosis-4 index was independently associated with the development of new hypertension (hazard ratio 4.279, 95

Objective: Since an increase in blood pressure is one of the most important risk factors for cardiovascular morbidity and mortality, appropriate blood pressure control is necessary to prevent target organ damages and cardiovascular diseases. We investigated changes in blood pressure control, target organ damage and cardiovascular risk factors of hypertensive subjects under antihypertensive medications from 2010 to 2019. Design and Methods: A total of 1679 and 1884 hypertensive subjects under antihypertensive medications (62.8 ± 9.8 and 65.8 ± 9.4 year-old, respectively) who visited our hospital for physical checkup in 2010 and 1019, respectively, were enrolled. Subjects were divided into two groups; controlled (blood pressure < 140/90mmHg) and not-controlled groups (blood pressure > = 140/90mmHg). Target organ damage defined as left ventricular hypertrophy (LVH) on electrocardiogram (Sokolow-Lyon voltage > 3.8 mV and/or Cornell product > 2440 mm ms) or decline of estimated glomerular filtration rate (eGFR; < 60 mL/min per 1.73 m2) and other cardiovascular risk factors were investigated. Results: The results are summarized in the table. Blood pressure control was generally improved during the 9 years though the mean age of subjects was increased. The prevalence of impaired kidney function but not LVH and the number of subjects with risk factors were increased during the period. Sub-analysis in 537 subjects who visited in both 2010 and 2019 were performed and similar results were obtained (data not shown). Conclusions: Although blood pressure control was improved, total management of hypertensive subjects was not appropriate. Management of risk factors other than hypertension as well as blood pressure control is necessary in hypertensive subjects for extension of healthy life expectancy.

Objective: More than half of all cardiovascular disease deaths have been attributed to high blood pressure. Although numerous factors are involved in the development of hypertension, excess dietary salt intake is quite important because it is a modifiable factor. Obviously, tracking alterations in salt intake with age is important for developing population-based strategies to lower salt intake. However, how salt intake changes with age at the individual level has not been intensively studied in the general population. Thus, the present study was designed to investigate changes in salt intake with age in individuals in the general population. Design and Methods: In this observational follow-up study, apparently healthy men and women age > 30 years who participated in a baseline medical checkup (2008–2009) at our center and had a medical checkup 10 years later (n = 2598) were enrolled. Salt intake was estimated by spot urine analysis. Yearly changes in salt intake were also assessed in participants with complete annual data over the course of 10 years from baseline (n = 1543). Results: The follow-up study demonstrated increased salt intake (8.8 ± 2.0 to 9.3 ± 2.1 g/day, P < 0.001) with increasing age (54.0 ± 9.7 to 64.0 ± 9.8 years). Salt intake increased year over year in participants who had a health checkup annually for the 10-year follow-up period (n = 1543; analysis of variance, P < 0.001). The increase in salt intake with age correlated with an increase in blood pressure. Then, regional levels of salt intake in the baseline period (between July 2008 and June 2009) and the period 10 years later (between July 2018 and June 2019) were compared using cross-sectional analyses. The propensity-matched model revealed similar regional levels of salt intake in the baseline period (8.9 ± 2.0 g/day, 55.8 ± 11.1 years, n = 5018) and at 10 years (8.8 ± 2.0 g/day, P = 0.21; 55.9 ± 13.0 years, P = 0.65, n = 5105). Conclusions: Dietary salt intake gradually increased with age in men and women in the general population during the 10-year follow-up period. This should be considered in devising for population-based strategies to lower dietary salt intake.

Purpose: Vascular endothelial dysfunction, an early change in atherosclerosis, is an independent risk factor for cardiovascular disease and is known to be reversible; RH-PAT (Reactive Hyperemia Peripheral Arterial Tonometry) can noninvasively measure vascular endothelial function. However, it is difficult to interpret the pathological significance of a single measurement because of many modifying factors such as diet, temperature, and medications. In this study, we aimed to investigate the effects of coronary risk factors and the presence of coronary artery disease on the diurnal variation of vascular endothelial function. Methods: Between May 2013 and May 2015, 498 patients (31% female, 19–94 years old, mean 66.7 ± 12.5 years) who were admitted to our hospital for cardiac catheterization, percutaneous coronary angioplasty, catheter ablation, or lower extremity peripheral angioplasty underwent RH-PAT examination (The Endo PAT 2000 system, Itamar Medical Ltd, Caesarea, Israel). The correlation between coronary risk factors and RH-PAT results was investigated. Correlations between coronary risk factors and RH-PAT results were also examined in patients who underwent coronary angiography. Results: The Reactive Hyperemia Index (RHI) was significantly lower in the group with smoking habit than in the nonsmoking group. Neither the number of coronary artery branches involved, the presence or absence of atrial fibrillation, nor the responsiveness to coronary spasm induction tests correlated significantly with the RHI. On the other hand, there was a significant difference between the morning and afternoon measurements in the group without coronary artery lesions, but no significant difference between the morning and afternoon measurements in the group with coronary artery lesions, regardless of the number of lesioned branches. Conclusions: Patients with a history of smoking, coronary artery lesions, and coronary spasms may have impaired diurnal variation in vascular endothelial function, suggesting that RH-PAT may be useful as an early indicator of coronary artery disease when measured at different time points.

Objective: Hypertension is one of the important risk factors for atherosclerosis leading to cardiovascular diseases. Although several factors have been reported as predictors of new onset of hypertension, the association of blood pressure (BP) variability in normotensive subjects with future development of hypertension is not intensively discussed. We tested the hypothesis that the yearly variability of BP in normotensive subjects predicts new onset of hypertension. Design and Methods: Subjects who participated in our annual physical check-up program for 5 years in a row during 2008 and 2013 were screened (screening period) and those under antihypertensive medication or with the average BP for the 5 visits ≧ 140/90 mmHg were excluded. The rest of 2006 participants (male = 1287) were eligible in the present study. Standard deviation (SD) and coefficient of variation (CV) of their systolic BP (SBP) during the 5 consecutive visits were calculated (screening period) and, then, they were followed up for the next 5 years (follow-up period). The onset of hypertension was defined as average BP during the follow-up period ≧ 140/90 mmHg or the use of antihypertensive medications. Results: The average, SD, and CV of SBP were 118.7 ± 10.0 mmHg, 7.44 ± 2.98 mmHg, and 6.30 ± 2.54%, respectively. During the follow-up, hypertension developed in 259 subjects, with the incidence being more frequent in male (n = 180, 14.0%) than female subjects (n = 79, 11.0%). In retrospective analysis, the average (128.7 ± 7.7 vs. 117.2 ± 9.5 mmHg, p < 0.001) and SD (8.05 ± 3.48 vs. 7.34 ± 2.89 mmHg, p < 0.001) were higher in subjects with than without future hypertension, whereas CV was not different in the both groups (6.28 ± 2.73 vs. 6.30 ± 2.51%). Non-adjusted odds ratio (OR) (95% confidence interval [CI]) of average, SD and CV for the incident hypertension were 1.169 (1.146–1.193), 1.078 (1.034–1.124) and 0.997 (0.947–1.050), respectively. Multivariate logistic regression analysis adjusted for age, gender, family history of hypertension, frequent alcohol consumption (six or seven times per week), current smoking, body mass index, heart rate, serum creatinine, fasting plasma glucose, LDL-cholesterol, and triglyceride at baseline demonstrated that average (OR [95%CI] = 1.193 [1.138–1.187]) and SD (1.058 [1.014–1.105]), but not CV (0.992 [0.941–1.046]), were associated with new onset hypertension. Similar results were obtained using diastolic BP (data not shown). Conclusions: In normotensive subjects, an increase in year-to-year variability as well as average of SBP may be a predictor of the new onset of hypertension. Careful interpretation of year-to-year BP variability is necessary for evaluation of future cardiovascular risk in normotensive individuals.

Objective: Dietary salt consumption is one of the most important modifiable factors in our lifestyle and restriction of dietary salt results in the reduction of blood pressure in previous studies. Excessive salt intake causes cardiovascular diseases independently of its effects on blood pressure. Since metabolic syndrome also increases a risk of cardiovascular disease, there may be some association between salt intake and metabolic syndrome. Therefore, we investigated a possible relationship between salt intake and future development of metabolic syndrome in the general population. Design and Methods: Consecutive 12,256 subjects without metabolic syndrome (male = 7,053, 52.1 ± 12.3 year-old) who visited our hospital for an annual physical check-up from April 2010 to March 2018 were enrolled. After baseline examination, subjects were followed up until March 2019 (median 1,582 days) with the endpoint being the development of metabolic syndrome. Metabolic syndrome was diagnosed according to the Japanese criteria (2005). Individual salt intake was estimated using a spot urine by a previously reported Tanaka method. Results: Salt intake was 8.7 ± 1.9 and 8.4 ± 1.8 g/day in male and female subjects, respectively, at baseline. During the follow-up period, 1,669 subjects developed metabolic syndrome (29.9 per 1,000 person-year) with the incidence being more frequent in male than female subjects (41.8 vs. 14.2 per 1,000 person-year). Non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of salt intake for the development of metabolic syndrome was 1.192 (1.164–1.221). Kaplan-Meier analysis where subjects were divided into gender-specific quartiles according to the baseline salt intake revealed that the incidence of metabolic syndrome were increased across the quartiles (19.5, 24.2, 33.1, and 43.9 per 1,000 person-years; logrank p < 0.001). Multivariate Cox proportional hazard analysis adjusted for age, gender, body mass index, systolic blood pressure, heart rate, serum creatinine, uric acid, fasting plasma glucose, low-density lipoprotein cholesterol, triglyceride, hemoglobin and current smoking habit at baseline revealed that salt intake predicted the new onset of metabolic syndrome (HR:1.055, 95%CI:1.028–1.082). Conclusions: Excessive salt intake is significantly associated with the new development of metabolic syndrome in the general population. The results suggest that salt restriction prevents cardiovascular diseases through the prevention of not only hypertension but also metabolic syndrome.

Abstract Increasing blood pressure variability (BPV) has been reported to be a strong predictor of cardiovascular events in patients with hypertension. However, the effects of BPV in the general population have not been intensively studied. The present study was designed to investigate a possible relationship between year‐to‐year BPV and hypertensive target organ damage (TOD) in a relatively low‐risk general population. A total of 5489 consecutive patients (mean age 58.6 ± 10.7 years) who visited our hospital for an annual physical checkup for five consecutive years during 2008–2013 were enrolled in this study. The average systolic and diastolic blood pressures and pulse pressure were calculated, as well as standard deviation, coefficient of variation, and average real variability in blood pressures. Cross‐sectional analysis was conducted and subjects without TOD at baseline (n = 3115) were followed up (median 1827 days) with the endpoint of TOD, defined as left ventricular hypertrophy on electrocardiogram or declining glomerular filtration rate. At baseline, BPV was closely associated with TOD. During follow‐up, left ventricular hypertrophy and declining glomerular filtration rate developed in 189 and 400 subjects, respectively. Although the standard deviation for systolic blood pressure and pulse pressure predicted future development of TOD in a univariate analysis, BPV was not a significant determinant of incident TOD in adjusted Cox hazard models. These results suggest that year‐to‐year BPV is a marker of the presence of TOD in the general population but does not independently predict future TOD.

Aims: Serum uric acid increases with metabolic disorders; however, whether the effects of uric acid on atherosclerosis are different in females and males has not been sufficiently evaluated. Therefore, this study compared the impact of uric acid on arterial stiffness and atherosclerosis between females and males. Methods: We enrolled 10196 untreated middle-aged subjects (46±8 years, 3021 females and 7175 males) who underwent periodic health check-ups. Serum uric acid levels were measured and arterial stiffness and atherosclerosis were assessed by the cardio-ankle vascular index (CAVI), carotid intima-media thickness (IMT), and plaque, using ultrasound imaging. Results: Females with increased arterial stiffness (CAVI ≥ 8.0) or carotid plaques had higher uric acid than those without (P＜0.0001), but males did not. In multivariable regression analyses including overall participants, uric acid was significantly associated with the CAVI, where sex interacted with uric acid. In sex-specific analyses, uric acid was significantly associated with the CAVI, but not with carotid IMT, in both sexes. However, logistic regression analyses revealed that serum uric acid was independently associated with the presence of carotid plaques in females. The exclusion of subjects with abdominal obesity or metabolic syndrome from the analysis did not alter the results in females. Conclusions: Serum uric acid was significantly associated with the CAVI in both sexes, but the interaction of sex was confirmed and associated with a carotid plaque only in females. These findings support the increased impact of serum uric acid on arterial stiffness and atherosclerosis in females.