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The spot urinary sodium-to-potassium (Na/K) ratio is a simple measure of salt loading and has been shown to be associated with elevated blood pressure (BP) in middle-aged and older adults. This study aimed to evaluate the association between the spot urinary Na/K ratio and BP in 457 healthy adolescents aged 12-15 years in a school-based setting. The mean urinary Na/K ratio was 4.99 ± 2.76, and no significant difference was found between the boys and girls. When the participants were stratified based on urinary Na/K ratio quartile, age- and sex-adjusted systolic and diastolic BP gradually increased as Na/K ratio increased (systolic BP: 106.1, 106.9, 108.2, and 111.5 mmHg, P trend  < 0.001; diastolic BP: 62.0, 62.4, 63.1, 64.3 mmHg, P trend  = 0.022). The systolic and diastolic BP were more closely associated with urinary Na/K ratio than with Na and K levels, as well as estimated daily salt intake. In the multiple regression analysis, the urinary Na/K ratio was significantly associated with systolic BP (β = 0.144, P < 0.001) and diastolic BP (β = 0.114, P = 0.015) independent of potential confounding factors. An additional subgroup analysis revealed that the BP of the group with both high salt intake (≥8.5 g/day) and high Na/K ratio (≥6.60) was significantly higher than that of the group with high salt intake alone (systolic BP, 115.0 vs. 109.1 mmHg, P < 0.001; diastolic BP, 66.0 vs. 62.5 mmHg, P = 0.017). These results suggest that the urinary Na/K ratio is associated with BP levels in healthy adolescents and may be useful for assessing salt loading and its effects on BP elevation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The renal tissue renin-angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear., Method: Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan., Results: Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin-angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity., Conclusion: These results reveal the previously unappreciated contribution of the intestinal tissue renin-angiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To evaluate blood pressure (BP)-lowering effects of Umezu polyphenols, polyphenols contained in Japanese plums, in a community-based sample by double-masked and placebo-controlled design., Methods: Seventy-two Japanese community-dwellers who were interested in prevention or control of their BP (preferably high-normal BP or grade I hypertension) but without antihypertensive medication were randomized into Umezu polyphenols or placebo groups. Each subject took 800 mg/day of Umezu polyphenols or placebo for 12 weeks, followed by a 2-week washout period. Their home and office BP were monitored for 14 weeks in a double-masked manner. We analyzed 56 subjects who met the inclusion criteria., Results: Home BP increased gradually in both the groups during the intervention period, while diastolic office BP insignificantly decreased in the intervention group. During the washout period, home systolic BP in the morning elevated only in the intervention group., Conclusions: The study failed to collect consistent evidence of a clear persistent hypotensive effect of Umezu polyphenols.

We examined the associations of obesity and high salt intake with blood pressure (BP) in a cross-sectional sample of 1679 healthy Japanese adolescents (827 females and 852 males) aged 12-18 years (mean age: 14.9 years) who had no history of treatment for hypertension, diabetes mellitus, or renal disease. Brachial arterial BP of the subject was measured at the left arm using a digital BP monitor with an appropriate cuff size. The weight status was evaluated by body mass index (BMI), and obesity was determined according to the age- and sex-specific cut-off values for adolescents. All subjects were interviewed by dietitians using a food frequency questionnaire to obtain data on their average daily salt intake. In the study subjects, obesity and high salt intake were associated with a significantly increased BP except for diastolic BP in females. In multiple regression analyses, both BMI (z-score) and salt intake were found to be major determinants of systolic BP and diastolic BP after adjustment for potential confounders, including age, sex, and serum lipid and glucose parameters. The association between salt intake and BP values was more pronounced among individuals with obesity than among those with normal weight. These results suggest that high salt intake is associated with BP elevation in healthy adolescents, and the association may become stronger by the presence or severity of obesity.

Pre-emptive medicine is a novel medical concept proposed in Japan that aims to precisely predict the onset and progression of diseases and to provide therapeutic interventions during early stages, before symptoms appear. The concept of pre-emptive medicine considers the time-course of a disease in each individual and seeks medical interventions to prevent disease progression. Suitable and promising targets for pre-emptive medicine are non-communicable diseases, including hypertension. Recent advances in genomic analysis, information technology, and artificial intelligence should make this medical concept feasible in the near future. In this review, we focused on pre-emptive medicine for hypertension, referring to concrete plans for the future direction of this research. The ultimate goal of pre-emptive medicine is to completely prevent the onset and progression of hypertension by precisely predicting the elevation of blood pressure and performing interventions to avoid it. The diagnostic processes of hypertension, from the standpoint of pre-emptive medicine, should include the detection of abnormal blood pressure regulation as the earliest manifestation of the disease, the depiction of the present status of hypertension in an individual ("nowcasting"), and a prediction of the future trajectory of the disease ("forecasting"). Novel therapeutic strategies for hypertension, from the standpoint of pre-emptive medicine, should aim for the regression of hypertension through early treatments and the remission of hypertension through intermittent intensive therapies. An efficient modification of lifestyle and therapies, according to the progression of hypertension, should be required. If pre-emptive medicine for hypertension becomes established, it would greatly contribute to the extension of a healthy lifespan, which cannot yet be satisfactorily achieved.

In recent years, several post-interventional analyses of large-scale randomized controlled clinical trials have given us a new concept regarding the risk management of hypertension and cardiovascular diseases. The beneficial effects of intensive treatments were extended even after the interventions ended. This phenomenon is known as "metabolic memory" or "legacy effect", and we recognized its clinical significance. A certain level of evidence in human and animal studies employing organ transplantation techniques has indicated that this type of "memory" resides in each organ and could be transferrable, erasable, and rewritable, which is similar to neuronal and immune "memory". In this review, we define this memory as "organ memory" and summarize the current picture and future direction of this concept. "Organ memory" can be observed in many clinical settings, including in the control of hypertension, diabetes mellitus, and dyslipidemia. Several intensive treatments were demonstrated to have the potential to rewrite "organ memory", leading to the curability of targeted diseases. "Organ memory" is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. Not only is the epigenetic change of key genes involved in the formation of "organ memory" but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms. Future studies should be directed toward the identification of the core unit of "organ memory" and its manipulation.

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

Objectives: Medications or lifestyle changes to prevent or improve hypertension often press considerable efforts on patients suffering from mild hypertension. Capsules including Umezu polyphenols (UP), polyphenols in Japanese plums, may help them to control their blood pressure (BP). The aim of this study is to evaluate the effectiveness of UP on BP and its safety., Methods: A total of 15 healthy workers without antihypertensive medication who had some concerns about their BP, preferably normal-high BP or hypertension level 1, were randomized in a double-blind manner into UP ingesting and placebo groups. Each subject was instructed to take four capsules daily for 12 weeks (daily UP dose, 800 mg for the UP ingesting group; and 0 mg for the placebo group). These subjects were followed for 12 weeks, and their BP both at home and at the examination site, as well as self-perceived quality-of-life outcomes and possible side effects, was monitored during that period. Group × time interactions on BP changes were examined., Results: All of the 15 subjects completed the 12-week intervention trial. The BP changes did not significantly differ between the UP ingesting and placebo groups, neither at the examination site nor at home. But during the study period, no adverse effects were observed., Conclusions: No remarkable effect of UP on BP was observed. However, a higher dose of UP was confirmed safe and high in adherence in this 12-week randomized controlled trial. Its effect on BP and other outcomes shall be confirmed in a larger sample.

CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.

In patients with severe hypertension, chronic heart failure or a history of stroke, the lower limit of autoregulation of cerebral blood flow (CBF) is shifted to higher levels of blood pressure (BP) than those observed in healthy subjects. The aim of pharmacotherapy for hypertensive patients with an impaired autoregulation of CBF should be to reduce BP while preserving an appropriate CBF. In the present study, 16 hypertensive patients who had had an episode of stroke more than 4 weeks previously were administered the angiotensin II (AT1) receptor antagonist losartan at daily doses of 25-100 mg for 4 weeks. Systolic and diastolic blood pressures were recorded for 24 h using an ambulatory BP monitoring system. CBF in both hemispheres of the cerebrum and cerebellum was quantified using single photon emission tomography with N-isopropyl-p-[123I]iodoamphetamine. At baseline, CBF was 29.7 +/- 6.7 ml/min/100 g in the cerebrum and 31.5 +/- 7.5 ml/min/100 g in the cerebellum. At the end of treatment, BP was lower, while CBF increased by 7.7% in the cerebrum, and remained at the baseline level in the cerebellum. Thus, CBF was preserved despite the reduction in BP. We consider the use of losartan is advantageous for hypertensive patients with a history of stroke in whom autoregulation of CBF is potentially impaired.

Previous works have shown that exaggerated blood pressure response to exercise is a valid risk marker for future hypertension, yet the use of an exercise test as a means of early prediction of hypertension still requires methodological development and confirmation. The purpose of this study was to determine abnormal ranges of blood pressure responses in relation to heart rate increase during exercise and to examine the clinical utility of exercise blood pressure measurement in evaluating individual risk for developing hypertension. We examined exercise test data from a population-based sample of 1033 nonmedicated normotensive men (mean age, 42.9+/-8.5 years; range, 20 to 59 years). Percentile curves of systolic and diastolic blood pressure responses to relative heart rate increments during submaximal exercise were constructed using a third-order polynomial model with multiple regression analysis. Of the original study sample, a cohort of 726 subjects was followed for hypertensive outcome for an average period of 4.7 years. Progression to hypertension, defined as a blood pressure of > or =140/90 mm Hg or the initiation of antihypertensive therapy, was found in 114 subjects (15.4%). Kaplan-Meier survival estimates showed that the cumulative incidence of hypertension increased progressively with higher percentiles of systolic and diastolic blood pressure response (both, P<0.01). A Cox proportional survival analysis revealed a significantly increased risk for developing hypertension associated with exaggerated blood pressure response to exercise after multivariable adjustments for traditional risk factors (relative risk, 3.8; 95% confidence interval, 2.3 to 6.1). These results suggest that an exaggerated blood pressure response to heart rate during exercise is predictive of future hypertension independent of other important risk factors and lend further support to the concept that blood pressure measurement during exercise test is a valuable means of identifying normotensive individuals at high risk for developing hypertension.

Background: The clinical implication of the tortuosity of white matter medullary arterioles has never been clarified precisely. We quantitatively investigated the relationship between such vascular tortuosity and the severity of hypertension (HT), which was graded according to the WHO classification., Methods: Forty-seven autopsied brains with age-adjusted stages of HT were evaluated. The largest tortuosity diameter and the largest vascular diameter in the same tortuous lesion were measured by light microscopic observation at the level of the corona radiata and centrum semiovale. A maximum ratio of these diameters was calculated for each patient., Results: Maximum ratios were found in almost all arterioles and were significantly increased according to the HT stages., Conclusions: Arteriolar tortuosity in the hemispheric white matter may reflect the severity of HT and be an indicator of hypertensive small vessel disease of the brain., (Copyright 2002 S. Karger AG, Basel)

Linear hyperintensity lesions, which are sometimes recognized in the cerebral white matter on T(2)-weighted magnetic resonance (MR) images, have never been studied from the clinical viewpoint. We refer to these lesions as linear hyperintensity objects (LHOs) and have investigated them quantitatively. Twenty-six consecutive patients underwent routine 1.5-Tesla MR imaging. LHOs were found in 24 patients. We measured the width and number of LHOs at the upper corona radiata level on T(2)-weighted images (repetition time: 4,500.0 ms, echo time: 96.0 ms) using a scale loupe. The diameters were significantly correlated with the stages of hypertension (WHO classification). The LHOs may associated with the dilated perivascular spaces of cortical medullary arteries and may become an indicator for hypertensive small vessel disease., (Copyright 2001 S. Karger AG, Basel)

Objectives: This study was designed to assess the clinical usefulness of an exaggerated blood pressure (BP) response to exercise (EBPR) in predicting the development of hypertension from a high-normal state., Background: Exaggerated BP response during both dynamic and isometric exercises are associated with increased risk of future hypertension, while the significance of these responses concerning the identification of individuals with high-normal BP who are prone to develop hypertension is unknown., Methods: The study population comprised a sample of 239 men with high-normal BP (aged 42.3 +/- 5.9 years) who underwent a symptom-limited bicycle ergometer exercise testing at baseline and then were followed for 5.1 years., Results: The Kaplan-Meier survival analysis showed that the subjects in the upper quartile of BP response to exercise had a significantly higher cumulative incidence of hypertension on follow-up than those in the middle two and lower quartiles (log-rank test, p < 0.05). Multivariate analysis using the Cox proportional hazards survival model showed that the EBPR was significantly and independently associated with the risk of developing hypertension after adjustment for some traditional risk factors for hypertension (RR = 2.31, 95% confidence interval = 1.45 to 6.25)., Conclusions: These findings suggest that an EBPR is an important risk factor for new-onset hypertension from a high-normal state and, thus, exercise testing can provide valid information that may help identify individuals with high-normal BP at a greater risk of future hypertension.

We investigated the effects of walking 10,000 steps/day or more on blood pressure and cardiac autonomic nerve activity in mild essential hypertensive patients. All subjects were males aged 47.0+/-1.0 (mean+/-SEM) years old. The original cohort consisted of 730 people in a manufacturing industry who measured the number of steps they walked each day using a pedometer. Eighty-three of these subjects walked 10,000 steps/day or more for 12 weeks. Thirty-two of these were hypertensives with systolic blood pressure (SBP) greater than 140 mmHg and/or diastolic blood pressure (DBP) greater than 90 mmHg. Thirty of these hypertensive subjects (HT) were examined twice, once during the pre- and once during the post-study period, for body mass index (BMI), maximal oxygen intake (Vo2max), blood pressure, heart rate (HR), and autonomic nerve activity by power spectral analysis of SBP and HR variability. In the HT group, walking 13,510+/-837 steps/day for 12 weeks lowered blood pressure (from 149.3+/-2.7/98.5+/-1.4 to 139.1+/-2.9/90.1+/-1.9 mmHg; p<0.01, respectively). In both the 34 normotensive controls and 17 hypertensive sedentary controls, blood pressure did not change. Walking also significantly lowered low-frequency fluctuations in SBP as an index of sympathetic nerve activity, from 1.324+/-0.192 to 0.738+/-0.154 mmHg2/Hz (p<0.05). VO2max rose significantly from 26.1+/-2.4 to 29.5+/-2.5 ml/kg/min (p<0.05). There were no changes in parasympathetic nerve activity, baroreceptor reflex sensitivity, or BMI. Our results indicate that walking 10,000 steps/days or more, irrespective of exercise intensity or duration, is effective in lowering blood pressure, increasing exercise capacity, and reducing sympathetic nerve activity in hypertensive patients.

Background: Protein C deficiency leads to reduced inhibition of coagulation and an increased likelihood of thrombosis. It is widely accepted that the most common syndromes associated with protein C deficiency are venous thrombosis and pulmonary thromboembolism, whereas arterial thrombosis is rare. Here we describe two patients with hypertension and hereditary heterozygous protein C deficiency who developed multiple lacunar infarcts., Case Descriptions: Patient 1 was a 46-year-old man with a history of hypertension who developed a right upper quadrantanopia and gradually progressive intellectual and behavioral deterioration. Patient 2 was a 61-year-old man with history of hypertension and two episodes of right-sided motor weakness who developed left sixth and seventh cranial-nerve palsies and reduced pinprick sensation in the right extremities. In both patients, magnetic resonance imaging revealed multiple small lesions in the pons as well as the bilateral basal ganglia, thalamus, corona radiata, and other subcortical structures, which are consistent with lacunar infarcts. Protein C activity and antigen levels were reduced to approximately one half of normal in these two patients, as well as in some of their family members who had no other serological or coagulation abnormalities. A diagnosis of heterozygous protein C deficiency type 1 was thus established., Conclusions: Although it remains uncertain whether protein C deficiency itself increases the risk of cerebral artery thrombosis, it may predispose a patient to develop multiple brain infarctions in association with hypertension.

In patients with severe hypertension, chronic heart failure or a history of stroke, the lower limit of autoregulation of cerebral blood flow (CBF) is shifted to higher levels of blood pressure (BP) than those observed in healthy subjects. The aim of pharmacotherapy for hypertensive patients with an impaired autoregulation of CBF should be to reduce BP while preserving an appropriate CBF. In the present study, 16 hypertensive patients who had had an episode of stroke more than 4 weeks previously were administered the angiotensin II (AT1) receptor antagonist losartan at daily doses of 25-100?mg for 4 weeks. Systolic and diastolic blood pressures were recorded for 24?h using an ambulatory BP monitoring system. CBF in both hemispheres of the cerebrum and cerebellum was quantified using single photon emission tomography with N-isopropyl-p-[123I]iodoamphetamine. At baseline, CBF was 29.7±6.7?ml/min/100?g in the cerebrum and 31.5±7.5?ml/min/100?g in the cerebellum. At the end of treatment, BP was lower, while CBF increased by 7.7%in the cerebrum, and remained at the baseline level in the cerebellum. Thus, CBF was preserved despite the reduction in BP. We consider the use of losartan is advantageous for hypertensive patients with a history of stroke in whom autoregulation of CBF is potentially impaired.Journal of Human Hypertension (2004) 18, 693-699. doi:10.1038/sj.jhh.1001735 Published online 6 May 2004 [ABSTRACT FROM AUTHOR]