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Sympathetic activation plays a critical role in the development of hypertension and cardiovascular disease, including heart failure and arrhythmias. Renal nerves contribute to the regulation of blood pressure and fluid volume through renal sympathetic efferent nerves, and to the modulation of sympathetic outflow through renal sensory afferent nerves. Previous studies including ours suggest that selective afferent renal denervation with preservation of efferent renal nerves can significantly decrease central sympathetic outflow in animal models of hypertension with renal damage. In Dahl salt-sensitive rats fed high salt diet from an early age, a model of hypertensive heart failure, this central sympathoinhibition by afferent renal denervation may attenuate the development of heart failure without significant blood pressure reduction. Accumulating clinical evidence supports the efficacy of renal denervation as an antihypertensive treatment. However, it remains important to clarify the appropriate indications and predictors of responders to renal denervation in the treatment of hypertension. Several clinical studies suggest beneficial effects of renal denervation in patients with heart disease, with or without hypertension, although most were not sham-controlled. In particular, some clinical studies have demonstrated that renal denervation reduces the incidence of atrial fibrillation or cardiovascular events even without a significant antihypertensive effect. It is essential to accumulate more insightful data in patients undergoing renal denervation, to establish the efficacy of renal denervation in patients with cardiovascular disease in the clinical setting, and to elucidate the therapeutic mechanisms of renal denervation and the renal nerves-linked pathophysiology of cardiovascular disease in basic research. (Figure presented.)

DOI： 10.1038/s41440-024-01776-7

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DOI： 10.1038/s41440-024-01781-w

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Accumulating evidence supports the efficacy of renal denervation (RDN) as an antihypertensive treatment. Additionally, several RDN clinical studies, including meta-analyses, have suggested that RDN may potentially have beneficial effects on left ventricular hypertrophy, diastolic function, and new-onset/recurrence of atrial fibrillation (AF), although most studies were not randomized sham-controlled. In particular, the effects of RDN on left ventricular hypertrophy and AF recurrence appear to be relatively evident. Sympathetic activation plays a critical role in the development of hypertension, hypertensive heart disease, and AF. Notably, several studies suggest the cardioprotective effects of RDN even in the absence of significant blood pressure reduction, probably due to its sympathoinhibitory effects. It is imperative to establish the efficacy of RDN in patients with hypertensive heart disease and/or AF, focusing on parameters of sympathetic activity in the clinical setting, including randomized sham-controlled trials. Moreover, further basic research is essential to elucidate the therapeutic mechanisms of RDN beyond blood pressure lowering and the renal nerves-linked pathophysiologies of hypertensive heart disease and AF. (Figure presented.)

DOI： 10.1038/s41440-024-01755-y

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Language：English   Publisher：Journal of General Internal Medicine  

Background: The triglyceride-glucose index (TyG index), calculated as the logarithmic product of fasting triglyceride and glucose concentrations, is recognized as a simple marker of insulin resistance. However, the association between the TyG index and future decline of renal function remains unclear in the general population. Objective: To investigate whether the TyG index was associated with future decline of renal function in the general population who had not progressed to chronic kidney disease stage G2. Design: Retrospective longitudinal observational cohort study. Participants: Individuals who received a population-based health checkup at JA Ehime Kouseiren Checkup Center from 2010 to 2019 (n = 134,007). Individuals without data of baseline fasting triglyceride or glucose levels, or baseline and follow-up data of estimated glomerular filtration rate (eGFR), or those with baseline eGFR < 60 mL/min/1.73 m2 were excluded. Main Measures: Future renal function decline, defined as a ≥ 25% decrease in eGFR from baseline. Key Results: Of 10,758 participants, 8,076 were classified into the low TyG index group (TyG index < 8.76, 1st to 3rd quartiles) and 2,682 into the high TyG index group (TyG index ≥ 8.76, 4th quartile). The mean follow-up period was 37.8 ± 23.6 months. The incidence rates of renal function decline were 0.31 and 0.69 per 100 person-years in the low and high TyG index groups, respectively. In multivariate Cox proportional hazard models, high TyG index was significantly associated with future renal function decline (hazard ratio 2.25, 95% CI 1.40–3.60). This association was consistent across subgroups stratified by age, sex, body mass index, baseline eGFR, and diagnosed hypertension, diabetes, or dyslipidemia. Conclusion: In the general population, high TyG index was associated with future renal function decline. The TyG index may be useful in identifying individuals at high risk for future renal function decline in the setting of health checkups. Graphical Abstract: (Figure presented.)

DOI： 10.1007/s11606-024-08809-4

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DOI： 10.1038/s41440-024-01689-5

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DOI： 10.1038/s41440-024-01635-5

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This study aimed to investigate whether renal denervation (RDN) reduces blood pressure and attenuates cardiac hypertrophy with decreasing sympathetic activity in spontaneously hypertensive rats (SHRs), a model of essential hypertension, during the established phase of hypertension. We performed RDN or sham operation in 15-weeks-old SHRs. Thirty days after RDN, mean blood pressure measured by telemetry, heart weight, left ventricular wall thickness assessed by echocardiography, and urinary norepinephrine levels were significantly decreased in the RDN group compared to the Sham group. Furthermore, oxidative stress, as indicated by thiobarbituric acid reactive substances, in the rostral ventrolateral medulla, a pivotal region regulating basal sympathetic tone, was significantly decreased in the RDN group. In conclusion, RDN reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in SHRs. These findings highlight the sympathoinhibitory effect of RDN and suggest that RDN may be a potential therapy for hypertensive cardiac hypertrophy. (Figure presented.)

DOI： 10.1038/s41440-024-01596-9

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Language：English   Publisher：The Japanese Circulation Society  

<p>The 87^thAnnual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of “New Challenge With Next Generation” the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.</p>

DOI： 10.1253/circj.cj-24-0127

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DOI： 10.1038/s41440-023-01518-1

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Language：English   Publisher：Scientific Reports  

Electrocardiographic left ventricular hypertrophy (LVH) could predict adverse renal outcomes in patients with hypertension. This study aimed to investigate the association between electrocardiographic LVH and future decline in renal function in the general population using a dataset of population-based health checkups from 2010 to 2019 including 19,825 participants. Electrocardiographic LVH was defined according to the Minnesota code. Renal function decline was defined as a decrease of ≥ 25% in the estimated glomerular filtration rate from baseline to < 60 mL/min/1.73 m2. Electrocardiographic LVH was found in 1263 participants at the baseline visit. The mean follow-up period was 3.4 ± 1.9 years. The incidence rates of renal function decline were 0.30 and 0.78 per 100 person-years in the non-LVH group and LVH groups, respectively. Electrocardiographic LVH was associated with the risk for renal function decline in the adjusted analysis (hazard ratio 1.69, 95% confidence interval 1.14–2.50, P = 0.009). This association was comparable across subgroups stratified by age, sex, body mass index, diagnosed hypertension, systolic blood pressure, hemoglobin A1c, and urinary protein. This study underscores the usefulness of electrocardiographic LVH to detect high-risk individuals for renal function decline in the setting of health checkups in the general population.

DOI： 10.1038/s41598-023-51085-1

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Total 276 manuscripts were published in Hypertension Research in 2022. Here our editorial members picked up the excellent papers, summarized the current topics from the published papers and discussed future perspectives in the sixteen fields. We hope you enjoy our special feature, 2023 update and perspectives in Hypertension Research.

DOI： 10.1038/s41440-023-01398-5

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Language：English   Publisher：International Heart Journal Association  

<p>Isolated cardiac sarcoidosis (iCS) is increasingly recognized; however, its prognosis and the efficacy of immunosuppressive therapy remain undetermined. We aimed to compare the prognosis of iCS and systemic sarcoidosis including cardiac involvement (sCS) under immunosuppressive therapy.</p><p>We retrospectively reviewed the clinical data of 42 patients with sCS and 30 patients with iCS diagnosed at Kyushu University Hospital from 2004 through 2022. We compared the characteristics and the rate of adverse cardiac events including cardiac death, fatal ventricular tachyarrhythmia, and heart failure hospitalization between the 2 groups. The median follow-up time was 1535 [interquartile range, 630-2555] days, without a significant difference between the groups. There were no significant differences in gender, NYHA class, or left ventricular ejection fraction. Immunosuppressive agents were administered in 86% of sCS and in 73% of iCS patients (<i>P</i> = 0.191). When analyzed only with patients receiving immunosuppressive therapy (sCS, <i>n</i> = 36; iCS, <i>n</i> = 21), the cardiac event-free survival was significantly lower in iCS than sCS (37% versus 79%, <i>P</i> = 0.002). Myocardial LGE content at the initial diagnosis was comparable in both groups. The disease activity was serially evaluated in 26 sCS and 16 iCS patients by quantitative measures of FDG-PET including cardiac metabolic volume and total lesion glycolysis, representing 3-dimensional distribution and intensity of inflammation in the entire heart. Although iCS patients had lower baseline disease activity than sCS patients, immunosuppressive therapy did not attenuate disease activity in iCS in contrast to sCS.</p><p>iCS showed a poorer response to immunosuppressive therapy and a worse cardiac prognosis compared to sCS despite lower baseline disease activity.</p>

DOI： 10.1536/ihj.24-166

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Language：English   Publisher：Nature Biomedical Engineering  

The mechanisms by which physical exercise benefits brain functions are not fully understood. Here, we show that vertically oscillating head motions mimicking mechanical accelerations experienced during fast walking, light jogging or treadmill running at a moderate velocity reduce the blood pressure of rats and human adults with hypertension. In hypertensive rats, shear stresses of less than 1 Pa resulting from interstitial-fluid flow induced by such passive head motions reduced the expression of the angiotensin II type-1 receptor in astrocytes in the rostral ventrolateral medulla, and the resulting antihypertensive effects were abrogated by hydrogel introduction that inhibited interstitial-fluid movement in the medulla. Our findings suggest that oscillatory mechanical interventions could be used to elicit antihypertensive effects.

DOI： 10.1038/s41551-023-01061-x

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DOI： 10.1038/s41440-023-01355-2

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A higher resting heart rate (RHR) is associated with an increased risk of cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The aim of this study was to investigate the association between RHR and cardiovascular events in T2DM patients with diabetic retinopathy and without known cardiovascular disease. We analyzed the association between RHR and cardiovascular events, including coronary, cerebral, renal and vascular events or cardiovascular death in T2DM patients with retinopathy and hyperlipidemia without prior cardiovascular events who were enrolled in the EMPATHY study. Data from 4746 patients were analyzed. The median RHR was 76 bpm. Patients were divided into four groups based on their baseline RHR (< 60, 60–69, 70–79, and ≥80 bpm). Patients with a higher RHR were more likely to be younger and had a higher body mass index, blood pressure value, HbA1c value, and estimated glomerular filtration rate and a lower B-type natriuretic peptide value; they also had a higher proportion of current smoking status, neuropathy, and nephropathy. After adjusting for confounders, including the aforementioned risk factors, a RHR of 70–79 bpm and a RHR ≥ 80 bpm were significantly associated with cardiovascular events (hazard ratio 1.50, 95% CI 1.03–2.20; and hazard ratio 1.62, 95% CI 1.11–2.36; respectively) compared to a RHR of 60–69 bpm. The analysis using restricted cubic splines indicated that the cardiovascular risk seemed to be similarly high when the RHR range was ≥70 bpm. In conclusion, in T2DM patients with diabetic retinopathy and without known cardiovascular disease, a high RHR, particularly ≥70 bpm, was associated with the risk of cardiovascular events compared to a RHR of 60–69 bpm. [Figure not available: see fulltext.].

DOI： 10.1038/s41440-023-01178-1

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Language：English   Publisher：The Japanese Circulation Society  

<p><b><i>Background:</i></b> Little is known about nationwide temporal trends in the clinical characteristics and treatment of dilated cardiomyopathy (DCM) in Japan.</p><p><b><i>Methods and Results:</i></b> We collected data regarding demographics, echocardiography, and treatment of DCM between 2003 to 2013 from Clinical Personal Records, a national registry organized by the Japanese Ministry of Health, Labour, and Welfare. Among the 40,794 DCM patients screened, 27,702 with left ventricular ejection fraction (LVEF) <50% and age ≥18 years were enrolled in this study and divided into 3 groups according to registration year: Group 1, 2003–2005 (10,006 patients); Group 2, 2006–2010 (11,252 patients); and Group 3, 2011–2013 (6,444 patients). Over time, there were decreases in age at registration (mean [±SD] 58.6±13.0 vs. 56.8±13.8 vs. 56.2±13.8 years; P<0.001) and LVEF (33.5±10.0% vs. 31.1±9.9% vs. 29.2± 9.7%; P<0.001), and an increase in patients with New York Heart Association Class III–IV (28.2% vs. 35.2% vs. 41.0%; P<0.001). The use of β-blockers (59.1% vs. 79.3% vs. 87.8%; P<0.001) and mineralocorticoid receptor antagonists (30.6% vs. 35.8% vs. 39.7%; P<0.001) increased over time. In multivariate analysis, male sex, systolic blood pressure, chronic kidney disease, hemoglobin, and registration year were positively associated, whereas age and LVEF were negatively associated, with β-blocker prescription.</p><p><b><i>Conclusions:</i></b> Although the clinical characteristics of DCM changed, the implementation of optimal medical therapy for DCM increased from 2003 to 2013 in Japan.</p>

DOI： 10.1253/circj.cj-22-0554

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Language：English   Publisher：Hypertension Research  

The pathogenesis of hypertension is multifactorial and highly complex. Basic research plays critical roles in elucidating the complex pathogenesis of hypertension and developing its treatment. This review covers recent topics in basic research related to hypertension in the following six parts: brain/autonomic nervous system, kidney, vascular system, potential treatments, extracellular vesicles, and gut microbiota. The brain receives afferent nerve inputs from peripheral organs, including the heart, kidneys, and adipose tissue, and humoral inputs from circulating factors such as proinflammatory cytokines and leptin, which are involved in the regulation of central sympathetic outflow. In the kidneys, changes in Wnt/β-catenin signaling have been reported in several hypertensive models. New findings on the renin-angiotensin-aldosterone system in the kidneys have also been reported. Sirtuin 6, which participates in various cellular functions, including DNA repair, has been shown to have protective effects on the vascular system. Skin water conservation, mediated by skin vasoconstriction and the accumulation of osmolytes such as sodium, has been found to contribute to hypertension. Studies of rivaroxaban and sodium-glucose cotransporter-2 inhibitors as drug repositioning candidates have been performed. Extracellular vesicles have been shown to be involved in novel diagnostic approaches and treatments for hypertension as well as other diseases. In gut microbiota studies, interactions between microbiota and antihypertensive drugs and potential pathophysiology linking microbiota and COVID-19 have been reported. It can be seen that inter-organ communication has received particular attention from these recent research topics. To truly understand the pathogenesis of hypertension and to develop treatments for conquering hypertension, interresearcher communication and collaboration should be further facilitated. [Figure not available: see fulltext.]

DOI： 10.1038/s41440-023-01176-3

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The activation of sympathetic nervous system plays a critical role in the development of hypertension. The input from afferent renal nerves may affect central sympathetic outflow; however, its contribution to the development of hypertension remains unclear. We investigated the role of afferent renal nerves in acute and chronic blood pressure regulation using normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Acute chemical stimulation of afferent renal nerves elicited larger increases in blood pressure and renal sympathetic nerve activity in young 9-week-old SHRSP compared to WKY. Selective afferent renal denervation (ARDN) and conventional total renal denervation (TRDN) ablating both afferent and efferent nerves in young SHRSP revealed that only TRDN, but not ARDN, chronically attenuated blood pressure elevation. ARDN did not affect plasma renin activity or plasma angiotensin II levels, whereas TRDN decreased both. Neither TRDN nor ARDN affected central sympathetic outflow and systemic sympathetic activity determined by neuronal activity in the parvocellular region of hypothalamic paraventricular nucleus and rostral ventrolateral medulla and by plasma and urinary norepinephrine levels, respectively. Renal injury was not apparent in young SHRSP compared with WKY, suggesting that renal afferent input might not be activated in young SHRSP. In conclusion, the chronic input from afferent renal nerves does not contribute to the development of hypertension in SHRSP despite the increased blood pressure response to the acute stimulation of afferent renal nerves. Efferent renal nerves may be involved in the development of hypertension via activation of the renin-angiotensin system in SHRSP.

DOI： 10.1038/s41440-022-01091-z

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Language：English   Publisher：ESC Heart Failure  

Aims: Cardiac rehabilitation (CR) is an evidence-based, secondary preventive strategy that improves mortality and morbidity rates in patients with heart failure (HF). However, the implementation and continuation of CR remains unsatisfactory, particularly for outpatients with physical frailty. This study investigated the efficacy and safety of a comprehensive home-based cardiac rehabilitation (HBCR) programme that combines patient education, exercise guidance, and nutritional guidance using information and communication technology (ICT). Methods and results: This study was a single-centre, open-label, randomized, controlled trial. Between April 2020 and November 2020, 30 outpatients with chronic HF (New York Heart Association II–III) and physical frailty were enrolled. The control group (n = 15) continued with standard care, while the HBCR group (n = 15) also received comprehensive, individualized CR, including ICT-based exercise and nutrition guidance using ICT via a Fitbit® device for 3 months. The CR team communicated with each patient in HBCR group once a week via the application messaging tool and planned the training frequency and intensity of training individually for the next week according to each patient's symptoms and recorded pulse data during exercise. Dietitians conducted a nutritional assessment and then provided individual nutritional advice using the picture-posting function of the application. The primary outcome was the change in the 6 min walking distance (6MWD). The participants' mean age was 63.7 ± 10.1 years, 53% were male, and 87% had non-ischaemic heart disease. The observed change in the 6MWD was significantly greater in the HBCR group (52.1 ± 43.9 m vs. −4.3 ± 38.8 m; P < 0.001) at a 73% of adherence rate. There was no significant change in adverse events in either group. Conclusions: Our comprehensive HBCR programme using ICT for HF patients with physical frailty improved exercise tolerance and improved lower extremity muscle strength in our sample, suggesting management with individualized ICT-based programmes as a safe and effective approach. Considering the increasing number of HF patients with frailty worldwide, our approach provides an efficient method to keep patients engaged in physical activity in their daily life.

DOI： 10.1002/ehf2.13934

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In 2021, 217 excellent manuscripts were published in Hypertension Research. Editorial teams greatly appreciate the authors’ contribution to hypertension research progress. Here, our editorial members have summarized twelve topics from published work and discussed current topics in depth. We hope you enjoy our special feature, “Update on Hypertension Research in 2021”.

DOI： 10.1038/s41440-022-00967-4

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Language：English   Publisher：International Journal of Cardiology  

Background: In patients with type 2 diabetes mellitus (T2DM) without known cardiovascular disease, the association between B-type natriuretic peptide (BNP) and cardiovascular events except for heart failure has not been elucidated. We aimed to investigate this association in high-risk T2DM patients. Methods: We analyzed the association between BNP and cardiovascular events, including coronary, cerebral, renal, and vascular events or cardiovascular death based on the single and serial measurement of BNP in T2DM patients with retinopathy and hyperlipidemia without known cardiovascular disease enrolled in the EMPATHY study. Results: Data from 4966 patients were analyzed for baseline BNP analysis. The median BNP value was 15.0 pg/mL. When analyzed in quartiles of baseline BNP (interquartile range 7.5–29.2 pg/mL), Q2, Q3, and Q4 were associated with cardiovascular events compared with Q1 (hazard ratio [HR]: Q2, 1.91 [P = 0.003]; Q3, 1.63 [P = 0.031]; Q4, 3.20 [P < 0.001]). The analysis of 12-month BNP showed similar associations. In serial BNP measurement, compared with low–low BNP group (baseline ≤35 pg/mL and 12-month ≤35 pg/mL), low–high BNP group as well as high–high BNP group was associated with cardiovascular events (HR: low–high, 2.05 [P = 0.004]; high–high, 2.07 [P = 0.001]) and non-renal cardiovascular events. High–low BNP group tended to be associated with non-renal cardiovascular events (HR vs low–low: 2.05 [P = 0.056]). Conclusions: BNP levels were associated with first cardiovascular events except for heart failure in T2DM patients with retinopathy and hyperlipidemia. Serial BNP measurement may be useful in further stratifying high-risk patients among this T2DM population.

DOI： 10.1016/j.ijcard.2022.03.049

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Language：English   Publisher：Clinical and Experimental Hypertension  

Introduction: Increased sympathetic output contributes to cardiac hypertrophy. Sympathoexcitation is induced by activating the cardiac sympathetic afferent nerves through transient receptor potential vanilloid 1 (TRPV1) in cardiac afferent endings. Brainstem nucleus tractus solitarius (NTS) receives the sensory cardiac afferent inputs. Brain-derived neurotrophic factor (BDNF) is released within NTS from sensory neurons in an activity-dependent manner. Additionally, BDNF in NTS tonically regulates sympathetic activity. Therefore, we hypothesized that TRPV1-expressing cardiac afferent nerves contribute to cardiac hypertrophy in accompany with an increased BDNF expression in NTS. Methods and Results: Abdominal aortic banding (AB) or sham operation was conducted in wild-type C57BL/6 J (WT-AB) and TRPV1 knockout mice (TRPV1 KO-AB). At 8 weeks post-operation, echocardiographic left ventricular wall thickness and heart weight/body weight ratio were significantly greater in WT-AB than WT-Sham mice, and these hypertrophic indexes were attenuated in TRPV1 KO-AB mice. Among the groups, left ventricular fractional shortening was not different. The protein levels of TRPV1 in heart and BDNF in NTS were significantly increased in WT-AB compared to WT-Sham mice, whereas BDNF expression in NTS was not increased by AB in TRPV1-KO mice. Chemical ablation of TRPV1-expressing cardiac afferents attenuated the AB-induced cardiac hypertrophy and increase in BDNF in NTS. Sympathetic activity analyzed using heart rate variability, and sympathoexcitatory responses to the stimulation of cardiac afferents were increased in WT-AB compared to WT-Sham mice. Conclusion: TRPV1-expressing cardiac afferent nerves may contribute to pressure overload-induced cardiac hypertrophy in accompany with the increased BDNF within NTS.

DOI： 10.1080/10641963.2022.2029470

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Renal nerves have critical roles in regulating blood pressure and fluid volume, and their dysfunction is closely related with cardiovascular diseases. Renal nerves are composed of sympathetic efferent and sensory afferent nerves. Activation of the efferent renal sympathetic nerves induces renin secretion, sodium absorption, and increased renal vascular resistance, which lead to increased blood pressure and fluid retention. Afferent renal sensory nerves, which are densely innervated in the renal pelvic wall, project to the hypothalamic paraventricular nucleus in the brain to modulate sympathetic outflow to the periphery, including the heart, kidneys, and arterioles. The effects of renal denervation on the cardiovascular system are mediated by both efferent denervation and afferent denervation. The first half of this review focuses on basic research using animal models of hypertension and heart failure, and addresses the therapeutic effects of renal denervation for hypertension and heart failure, including underlying mechanisms. The second half of this review focuses on clinical research related to catheter-based renal denervation in patients with hypertension. Randomized sham-controlled trials using second-generation devices, endovascular radiofrequency-based devices and ultrasound-based devices are reviewed and their results are assessed. This review summarizes the basic and clinical evidence of renal denervation to date, and discusses future prospects and potential developments in renal denervation therapy for cardiovascular diseases.

DOI： 10.1038/s41440-021-00827-7

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Abstract: Renal denervation is a promising new non-pharmacological treatment for resistant hypertension. However, there is a lack of data from Asian patients. The REQUIRE trial investigated the blood pressure-lowering efficacy of renal denervation in treated patients with resistant hypertension from Japan and South Korea. Adults with resistant hypertension (seated office blood pressure ≥150/90 mmHg and 24-hour ambulatory systolic blood pressure ≥140 mmHg) with suitable renal artery anatomy were randomized to ultrasound renal denervation or a sham procedure. The primary endpoint was change from baseline in 24-hour ambulatory systolic blood pressure at 3 months. A total of 143 patients were included (72 renal denervation, 71 sham control). Reduction from baseline in 24-hour ambulatory systolic blood pressure at 3 months was not significantly different between the renal denervation (−6.6 mmHg) and sham control (−6.5 mmHg) groups (difference: −0.1, 95% confidence interval −5.5, 5.3; p = 0.971). Reductions from baseline in home and office systolic blood pressure (differences: –1.8 mmHg [p = 0.488] and −2.0 mmHg [p = 0.511], respectively), and medication load, did not differ significantly between the two groups. The procedure-/device-related major adverse events was not seen. This study did not show a significant difference in ambulatory blood pressure reductions between renal denervation and a sham procedure in treated patients with resistant hypertension. Although blood pressure reduction after renal denervation was similar to other sham-controlled studies, the sham group in this study showed much greater reduction. This unexpected blood pressure reduction in the sham control group highlights study design issues that will be addressed in a new trial. Clinical trial registration: NCT02918305 (http://www.clinicaltrials.gov).

DOI： 10.1038/s41440-021-00754-7

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Intensive lipid-lowering therapy is recommended in individuals exhibiting type 2 diabetes mellitus (T2DM) with microvascular complications (as high-risk patients), even without known cardiovascular disease (CVD). However, evidence is insufficient to stratify the patients who would benefit from intensive therapy among them. Hypertension is a major risk factor, and uncontrolled blood pressure (BP) is associated with increased CVD risk. We evaluated the efficacy of intensive vs. standard statin therapy for primary CVD prevention among T2DM patients with retinopathy stratified by BP levels. We used the dataset from the EMPATHY study, which compared intensive statin therapy targeting low-density lipoprotein cholesterol (LDL-C) levels of <70 mg/dL and standard therapy targeting LDL-C levels ranging from ≥100 to <120 mg/dL in T2DM patients with retinopathy without known CVD. A total of 4980 patients were divided into BP ≥ 130/80 mmHg (systolic BP ≥ 130 mmHg and/or diastolic BP ≥ 80 mmHg, n = 3335) and BP < 130/80 mmHg (n = 1645) subgroups by baseline BP levels. During the median follow-up of 36.8 months, 281 CVD events were observed. Consistent with previous studies, CVD events occurred more frequently in the BP ≥ 130/80 mmHg subgroup than in the BP < 130/80 mmHg subgroup (P < 0.001). In the BP ≥ 130/80 mmHg subgroup, intensive statin therapy was associated with lower CVD risk (HR 0.70, P = 0.015) than standard therapy after adjustment. No such association was observed in the BP < 130/80 mmHg subgroup. The interaction between BP subgroup and statin therapy was significant. In conclusion, intensive statin therapy targeting LDL-C < 70 mg/dL provided benefits in primary CVD prevention when compared with standard therapy among T2DM patients with retinopathy and BP ≥ 130/80 mmHg.

DOI： 10.1038/s41440-021-00734-x

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intensive lipid-lowering therapy is recommended in type 2 diabetes mellitus (T2DM) patients with target organ damage. However, the evidence is insufficient to stratify the patients who will benefit from the intensive therapy among them. High visit-to-visit variability in systolic blood pressure (SBP) is associated with increased risk of cardiovascular events. We investigated the effectiveness of intensive versus standard statin therapy in the primary prevention of cardiovascular events among T2DM patients with retinopathy stratified by visit-to-visit SBP variability. METHODS: The standard versus intensive statin therapy for hypercholesterolemic patients with diabetic retinopathy study was the first trial comparing statin intensive therapy targeting low-density lipoprotein cholesterol (LDL-C) <70 mg/dl and standard therapy targeting LDL-C ≥100 to <120 mg/dl in T2DM patients with retinopathy without known cardiovascular disease. Using this dataset, we divided the patients into two subpopulations based on standard deviation (SD) and average real variability (ARV) of clinic SBP within the initial 6 months. RESULTS: In a total of 4899 patients, 240 composite cardiovascular events were observed during a median follow-up of 37.3 months. In multivariable-adjusted model comparing intensive versus standard therapy, the hazard ratios for composite cardiovascular events were 0.64 (95% CI 0.45-0.90) and 1.21 (95% CI 0.82-1.80) in patients with high and low SBP variability as defined by SD, respectively. Interaction between SBP variability and statin therapy was significant (P = 0.018). The analysis using ARV of SBP showed similar results. CONCLUSION: Statin intensive therapy targeting LDL-C <70 mg/dl had benefits in primary prevention of cardiovascular events compared with standard therapy among T2DM patients with retinopathy having high, but not low, visit-to-visit SBP variability.

DOI： 10.1097/HJH.0000000000002823

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Language：Japanese   Publisher：Japan Society of Neurovegetative Research  

<p>The renin-angiotensin system (RAS) independently exists in the brain apart from the circulating RAS, and an increase in brain RAS activity causes sympathetic hyperactivity. Renin, the rate-limiting enzyme of RAS, has two distinct isoforms: intracellular renin is the dominant isoform in the brain and transcribed from an alternative promoter-first exon, whereas secreted renin is the classical isoform expressed in the kidney. We generated the intracellular renin knockout mice to investigate the role of brain-specific intracellular renin in cardiovascular and metabolic control. Surprisingly, intracellular renin-deficient mice exhibited hypertension and increased sympathetic nerve activity. Further, intracellular renin-deficient mice gained significantly less weight than control mice when fed high-fat diet. Intracellular renin-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus and an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. Interestingly, despite an ablation of intracellular renin, expression of secreted renin was increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of brain RAS activity by a coordinated regulation of the renin isoforms, with intracellular renin tonically inhibiting expression of secreted renin under baseline conditions. Impairment of this control mechanism may cause hypertension and resistant to obesity through sympathoexcitation.</p>

DOI： 10.32272/ans.58.1_086

CiNii Research

Language：Japanese   Publisher：一般社団法人 日本循環器学会  

DOI： 10.1253/jjcsc.30.0_11

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II-induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II-induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II-induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II-induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II-induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.

DOI： 10.1161/HYPERTENSIONAHA.119.14400

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Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Hypertension is associated with systemic inflammation. The activation of the sympathetic nervous system is critically involved in the pathogenesis of hypertension. Brain perivascular macrophages (PVMs) can be affected by circulating inflammatory cytokines, and the contribution of brain PVMs to sympathoexcitation has been demonstrated in a heart failure model. We thus investigated whether brain PVMs contribute to the development of hypertension through sympathoexcitation. Stroke-prone spontaneously hypertensive rats (SHRSP) developed hypertension over an 8-week period from 4 to 12 weeks of age. The number of brain PVMs and plasma interleukin-1β levels significantly increased at the ages of 8 and 12 weeks in SHRSP compared with normotensive Wistar-Kyoto rats (WKY). To determine the contribution of brain PVMs to blood pressure elevation, we intracerebroventricularly injected liposome-encapsulated clodronate, which eliminates macrophages by inducing apoptosis, into 8-week-old rats; we then assessed its effects in 10-week-old rats. Clodronate treatment attenuated the increase in mean blood pressure in SHRSP but not in WKY. Clodronate treatment reduced the depressor effect of hexamethonium, an index of sympathetic activity; it also reduced neuronal activity in sympathetic regulatory nuclei such as the hypothalamic paraventricular nucleus and rostral ventrolateral medulla and reduced the expression of cyclooxygenase-2 and prostaglandin E2, a downstream pathway in activated macrophages, in SHRSP but not in WKY. Furthermore, clodronate treatment attenuated the increase in blood pressure and renal sympathetic nerve activity in response to an acute intravenous injection of interleukin-1β in WKY. In conclusion, brain PVMs contribute to the development of hypertension via sympathetic activation. PVMs may be activated by increased levels of circulating interleukin-1β.

DOI： 10.1038/s41440-019-0333-4

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/hjh.0000000000002091

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Language：English   Publishing type：Research paper (scientific journal)  

Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin–angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-b ^Null mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-b ^Null mice are unknown. Fluid intake was similar in control and Ren-b ^Null mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate–salt. Dehydration promoted increased water intake in Ren-b ^Null mice, particularly after deoxycorticosterone acetate–salt. Ren-b ^Null and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-b ^Null mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-b ^Null mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-b ^Null mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.

DOI： 10.1161/hypertensionaha.117.09923

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/hr.2017.14

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Other Link： https://www.nature.com/articles/hr201714

Language：Japanese   Publisher：日本循環制御医学会  

DOI： 10.11312/ccm.38.191

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

The renin–angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b–deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b–deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b–deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension.

DOI： 10.1161/hypertensionaha.116.08242

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.14814/phy2.12514

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Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Ovid Technologies (Wolters Kluwer Health)  

DOI： 10.1097/hjh.0b013e328364a2a1

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Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.3109/10641963.2012.681084

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.3109/10641963.2012.666603

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Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Heart Journal (Japanese Heart Journal)  

Reactive oxygen species (ROS) in rostral ventrolateral medulla (RVLM) of brainstem contribute to sympathoexcitation and are critically involved in the pathogenesis of hypertension. Baroreflex sensitivity (BRS) is a valuable prognostic parameter of the autonomic nervous system, and is impaired in hypertension. The aim of the present study was to determine whether or not a chronic reduction of ROS in the RVLM improves impaired BRS in hypertensive rats. We transfected adenovirus vectors encoding either manganese superoxide dismutase (AdMnSOD) or <i>β</i>-galactosidase (AdLacZ) into the RVLM of stroke-prone spontaneously hypertensive rats (SHRSP). We measured BRS using the spontaneous sequence method. BRS was significantly lower in SHRSPs than in Wistar-Kyoto rats. In the AdMnSOD-transfected SHRSP, blood pressure, heart rate, and sympathetic nervous system activation were significantly decreased from day 5 after the gene transfer. BRS in the AdMnSOD-transfected SHRSP was significantly increased from day 4 after the gene transfer with the reduction of ROS in the RVLM. Furthermore, in the AdMnSOD-transfected SHRSP, intravenous infusion of atropine dramatically decreased BRS. In contrast, in the AdLacZ-transfected SHRSP, atropine did not decrease BRS. These results suggest that chronic reduction of ROS in the local RVLM improves the impaired BRS in SHRSP through inhibition of the sympathetic component.

DOI： 10.1536/ihj.53.193

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CiNii Research

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Circulation Society  

<b><i>Background:</i></b> The rostral ventrolateral medulla (RVLM) in the brainstem is responsible for regulation of the sympathetic nervous system. In the RVLM, nitric oxide (NO)-mediated γ-amino butyric acid (GABA) is a major sympathoinhibitory amino acid neurotransmitter and superoxide is a major sympathoexcitatory factor. In this study, we investigated whether or not NO-mediated GABA release is involved in superoxide-induced sympathoexcitation in the RVLM of hypertensive rats. <b><i>Methods and Results:</i></b> For our model hypertensive rats with sympathoexcitation, we used stroke-prone spontaneously hypertensive rats (SHRSP). GABA levels in the RVLM were measured by in vivo microdialysis. Microinjection of tempol, a superoxide scavenger, into the RVLM decreased arterial pressure (AP), heart rate (HR), and renal sympathetic nerve activity (RSNA) with an increase in GABA release in the RVLM. Microinjection of <i>N</i>^G-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor, into the RVLM increased AP, HR, and RSNA with a decrease in GABA release in the RVLM. Prior microinjection of L-NMMA into the RVLM attenuated the tempol-induced changes in AP, HR, RSNA, and GABA release in the RVLM. Microinjection of bicuculline, a GABA receptor blocker, into the RVLM attenuated the tempol- and L-NMMA-induced changes in AP, HR, and RSNA. <b><i>Conclusions:</i></b> The findings suggest that reduction of NO-mediated GABA release in the RVLM is partly involved in superoxide-induced sympathoexcitation of SHRSP.  (Circ J 2012; 76: 2814–2821)<br>

DOI： 10.1253/circj.cj-12-0399

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CiNii Research

Country：Japan  

Country：Japan  

Country：Japan  

Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：軽井沢   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：北九州   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：高松   Country：Japan  

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：高松   Country：Japan  

Language：English   Presentation type：Symposium, workshop panel (public)  

Country：United States  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publisher：(株)北隆館  

腎交感神経は、中枢から腎臓に向かう遠心路と、腎臓から中枢に入力する求心路から成る。慢性的な遠心性腎神経の活性化によって、ナトリウム・水の再吸収亢進、RAAS亢進、腎血管抵抗上昇による腎血流低下、腎障害が起こり、血圧上昇に寄与する。求心性腎神経の急性刺激により、脳を介して全身の交感神経活動は亢進し、血圧や心拍数は上昇する。腎デナベーション(Renal Denervation:RDN)による主な降圧機序として、(1)腎障害を伴う高血圧:求心性腎神経の除神経による脳を介した交感神経出力低下、(2)腎障害は軽度で交感神経活性化を伴う高血圧:遠心性腎神経の除神経による循環RAAS/血管収縮の抑制、が示唆される。(著者抄録)

Language：Japanese   Publisher：(株)北隆館  

腎交感神経は、中枢から腎臓に向かう遠心路と、腎臓から中枢に入力する求心路から成る。慢性的な遠心性腎神経の活性化によって、ナトリウム・水の再吸収亢進、RAAS亢進、腎血管抵抗上昇による腎血流低下、腎障害が起こり、血圧上昇に寄与する。求心性腎神経の急性刺激により、脳を介して全身の交感神経活動は亢進し、血圧や心拍数は上昇する。腎デナベーション(Renal Denervation:RDN)による主な降圧機序として、(1)腎障害を伴う高血圧:求心性腎神経の除神経による脳を介した交感神経出力低下、(2)腎障害は軽度で交感神経活性化を伴う高血圧:遠心性腎神経の除神経による循環RAAS/血管収縮の抑制、が示唆される。(著者抄録)

Language：Japanese   Publisher：(一社)日本内分泌学会  

Language：Japanese   Publisher：(一社)日本体力医学会  

Language：Japanese   Publisher：(株)ライフメディコム  

高血圧の成因や病態に交感神経活動の亢進が関与しており、腎交感神経を除神経する腎デナベーション(renal denervation:RDN)治療が注目されている。腎交感神経は、中枢から腎臓に向かう遠心路と、腎臓から中枢に入力する求心路からなる。慢性的な遠心性腎神経の活性化によって、ナトリウム・水の再吸収亢進、レニン・アンジオテンシン・アルドステロン系(RAAS)亢進、腎血管抵抗上昇による腎血流低下、腎障害が起こり、血圧上昇に寄与する。求心性腎神経の急性刺激により、脳を介して全身の交感神経活動は亢進し、血圧や心拍数は上昇する。腎障害を伴う高血圧モデルにおいては、求心性腎神経が活性化しており、求心性腎神経の除神経による脳を介した交感神経出力低下が、RDNによる降圧機序として示されている。一方、腎障害は顕著ではないものの交感神経活性化を伴う高血圧モデルにおいては、遠心性腎神経の除神経による循環RAAS/血管収縮の抑制が、RDNによる主な降圧機序として示されている。これらより、慢性腎臓病合併の高血圧や、肥満・ストレス・食塩過剰摂取といった交感神経活性化を伴う高血圧の病態において、RDNの有効性が支持される。(著者抄録)

Language：Japanese   Publisher：(一社)日本循環器学会  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J02858&link_issn=&doc_id=20210826140002&doc_link_id=10.1253%2Fjjcsc.30.0_11&url=https%3A%2F%2Fdoi.org%2F10.1253%2Fjjcsc.30.0_11&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：日本自律神経学会  

レニン・アンジオテンシン系(RAS)は脳内にも存在し,脳内RASの亢進は交感神経活性化を来す.RASの律速酵素レニンには,分泌型レニンと細胞内レニン(細胞外に分泌されず細胞内に留まる)のアイソフォームがあり,脳内では細胞内レニンが優位に発現する.興味深いことに,細胞内レニンノックアウトにより,交感神経活性化を伴って血圧は上昇し,高脂肪食誘発性体重増加は抑制された.さらには脳内の分泌型レニンの増加を介した脳内RAS亢進がみられた.これらより,細胞内レニンは脳内において分泌型レニン発現に対して抑制的に働き,下流のアンジオテンシン産生を抑制することで,脳内RASという中枢性循環・代謝調節機構を制御している可能性が示唆された.(著者抄録)

Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J00586&link_issn=&doc_id=20210419300018&doc_link_id=10.32272%2Fans.58.1_086&url=https%3A%2F%2Fdoi.org%2F10.32272%2Fans.58.1_086&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：Japanese   Publisher：(株)文光堂  

Language：Japanese   Publisher：日本循環制御医学会  

Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J00631&link_issn=&doc_id=20180208300005&doc_link_id=%2Fde5circc%2F2017%2F003803%2F006%2F0191-0192%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fde5circc%2F2017%2F003803%2F006%2F0191-0192%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Publisher：Journal of Hypertension  

DOI： 10.1097/HJH.0000000000000003

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