bluuebunny/crossref_metadata_2025 huggingface dataset:
S-11-1: ARTERIAL STIFFNESS AND HEMODYNAMIC PARAMETERS FOR THE EARLY PREDICTION OF PREECLAMPSIA: A PROSPECTIVE COHORT STUDY
Authors: Daskalopoulou Stella S. , Phan Kim , Schiller Ian , Dendukuri Nandini , Gomez Yessica Haydee , Gorgui Jessica , Messidi Amira El , Abenhaim Haim , Rahme Elham , Gagnon Robert
Published: January 2023

Objective:

Preeclampsia is a leading complication of pregnancy, yet there remains no reliable clinical tool for its early prediction. Assessment of vascular dysfunction, a central feature of preeclampsia, by arterial stiffness and hemodynamic measurements could be a promising tool for preeclampsia prediction.

This study aimed to evaluate 1) arterial stiffness and hemodynamic parameters as an early predictive tool for preeclampsia, and 2) longitudinal changes in these parameters and identify changepoints prior to preeclampsia onset.

Design and method:

In this prospective longitudinal cohort study of women with singleton high-risk pregnancies (n = 236), arterial stiffness (carotid-femoral pulse wave velocity, cfPWV) and wave reflection (augmentation index [AIx], and time to wave reflection [T1R]) were assessed using applanation tonometry (SphygmoCor, AtCor) at 10–13 weeks and repeated every 4 weeks throughout pregnancy. Circulating angiogenic biomarkers (soluble fms-like tyrosine kinase, and placental growth factor) were measured (Quantikine, R&D Systems) at each trimester, and a bilateral uterine artery Doppler (UAD) was performed in the second trimester. The predictive ability of arterial stiffness was compared to that of peripheral blood pressure, UAD indices, as well as angiogenic biomarkers.

Furthermore, changepoints in cfPWV, AIx, and T1R were compared between women who did and did not subsequently develop preeclampsia.

Results:

A first-trimester 1 m/s increase in cfPWV was associated with 64% increased odds (p < 0.05), while a 1 ms increase in T1R with 11% decreased odds for preeclampsia (p < 0.01). The area under the curve of arterial stiffness, blood pressure, ultrasound indices, and angiogenic biomarkers was 0.84, 0.68, 0.66, and 0.64, respectively (Figure).

A changepoint in cfPWV was detected at 14–17 weeks. cfPWV then increased in women who subsequently developed preeclampsia but decreased in women who did not; a 1.2 m/s difference in cfPWV between the groups was observed at 22–25 weeks. An increase in AIx was noted at 18–21 weeks while at 30–33 weeks in women who did and did not develop preeclampsia, respectively.

Conclusions:

Arterial stiffness and wave reflection were higher in the first trimester and throughout pregnancy in women destined to develop preeclampsia. These indices predicted preeclampsia earlier (in the first trimester) and with greater ability than blood pressure, UAD, and/or angiogenic biomarkers. Furthermore, altered vascular adaptations in the early second trimester were observed in women who subsequently developed preeclampsia. These findings demonstrate the potential clinical utility of arterial stiffness and hemodynamic parameters as an early screening tool for preeclampsia, which can be used to inform clinical management of high-risk pregnancies.
S-12-1: PAST AND FUTURE OF HYPERTENSION RESEARCH
Authors: Mancia Giuseppe
Published: January 2023

Research on hypertension has achieved, in the last few decades, important results on the pathophysiology, diagnosis and treatment of the high blood pressure (BP) condition. However, as listed in the 2018 European guidelines, several aspects remain unclarified either because they have not been explored by properly designed studies or because data remain controversial.

This presentation will discuss some of the questions that represent important unmet needs for hypertension research. One, absence of randomized evidence-based trials on the benefit of antihypertensive treatment in important clinical conditions such as white coat hypertension, masked hypertension, resistant hypertension, hypertension of the very elderly people (e.g. nonagenarians) and hypertensives classifiable as frail because of the high number of comorbidities and poor life expectancy. Two, hypertension of relatively young people (e.g. < 45 or 40 years) in whom low event incidence prevents the performance of event-based trials, making prevention or progression of subclinical organ damage probably the only reliable and feasible approach. Three, the benefit of funding treatment on out-of-office (ambulatory and/or home) BP either as an alternative or an addition to classical office BP reduction, a fundamental therapeutic issue never addressed in the past. Four, the BP threshold at which to start treatment in naive hypertensives and the goal BP value to try to reach in different demographic and clinical hypertension subgroups. And finally, the problem of residual risk in apparently well treated hypertensive individuals, i.e. their persistence at a risk level clearly higher than that of the control population. A final consideration will be that assessing this issue by randomized trials will probably be difficult and that future research will thus have to rely more and more frequently on observational studies which can now be based on large population data-bases that extend over many years and can, via extensive information and high quality analysis, substantially reduce the risk of the risk of confounding associated with this approach.
S-13-5: UPDATES ON FAMILIAL HYPERALDSOTERONISM
Authors: Stowasser Michael
Published: January 2023

The first reported (Sutherland et al. 1966) form of familial primary aldosteronism (PA) involved a father and son and was glucocorticoid-remediable (familial hyperaldosteronism type I, FH-I). In 1992, Lifton and colleagues elucidated its causation, a hybrid gene mutation composed of CYP11B1 (encoding 11beta-hydroxylase) regulatory sequences and CYP11B2 (aldosterone synthase) coding sequences causing ACTH-regulated aldosterone overproduction and hypertension, both readily controlled by low-dose glucocorticoid administration. Expression of aldosterone synthase activity within zona fasciculata (ZF) explained overproduction of hybrid steroids, 18-hydroxy- and 18-oxocortisol. Since 2011, PA-causing germline mutations in another four genes (three associated with FH) have been reported. While three encode cation channels (KCNJ5, CACNA1H and CACNA1D), one encodes an anion channel (CLCN2).

FH-III is caused by inheritance of gain-of-function mutations in KCNJ5, encoding an inwardly rectifying potassium channel (GIRK-4). Depending on the exact mutation involved, phenotype varies from very severe (profound PA, hybrid steroid elevation and ZF hyperplasia and requiring bilateral adrenalectomy to control hypertension) to mild (absence of above with PA controllable with spironolactone). Most pedigrees demonstrate early-onset hypertension. Mutations reduce selectivity of GIRK-4 to potassium, permitting entry of sodium into the adrenal cortical cell, which results in cell depolarization and calcium influx, leading to increased expression of CYP11B2 and aldosterone synthesis.

A gain-of-function mutation in CACNA1H, encoding a T-type voltage-gated calcium channel, was found in five of 40 subjects with early-onset PA and three relatives with early-onset hypertension (FH-IV). Adrenals appeared normal on imaging. The mutation shifts activation of zona glomerulosa (ZG) cells to a more hyperpolarized potential and slows inactivation, putatively resulting in increased calcium influx and aldosterone production.

Germline mutations in CACNA1D, encoding an L-type voltage-gated calcium channel highly expressed in ZG, were identified in two of 100 individuals with early-onset PA. Both occurred de novo, and were associated with seizures and a variety of neurological abnormalities (PASNA). Both mutations cause channel activation at less depolarized membrane potentials, and one nearly abolished channel inactivation.

In a large Australian family with FH-II, a mutation was found in CLCN2 encoding a chloride channel, ClC-2. CLCN2 mutations were found in another seven of 80 individuals with early-onset PA. A concurrent report found a CLCN2 mutation in one of 12 subjects with early-onset PA. PA due to CLCN2 mutations responds well to medical treatment. In the adrenal, ClC-2 localizes predominantly to ZG and mutations predispose cell depolarization, leading to calcium influx via activation of voltage-gated calcium channels and increased aldosterone production.
S-14-2: AMELIORATION OF THE DISCREPANCY BETWEEN PHYSICIANS AND PATIENTS IN HYPERTENSION MANAGEMENT
Authors: Hasebe Naoyuki
Published: January 2023

Although the control rate of hypertension has gradually improved over the last 40 years in Japan, it is still unsatisfactory low at only around 48% of male and 50% of female patients. Despite remarkable advances in the diagnosis and treatment of hypertension, countermeasures against hypertension are still insufficient. This hypertension paradox is a recent serious clinical issue in Japan. I named this unfortunate clinical condition of neglecting uncontrolled hypertension as feigning ignorance of hypertension. The feigning ignorance of hypertension is caused by patients who don’t want to listen to their doctor's negative comments, is exacerbated by doctors or medical providers who don’t want to say what their patients don’t want to hear. More than 70% of causal factors of hypertension paradox may be attributed to feigning ignorance.

We conducted a web-based survey, named PARADOX and studied patients (n = 881) and physicians (n = 541) involved in hypertension treatment. Approximately 80% of physicians reported that they fully or sufficiently provided education to patients about hypertension treatment. In contrast, only 40 to 50% of patients considered those topics to have been fully or sufficiently covered by doctors at the initial consultation. The largest discrepancy was observed in the topic of target blood pressure and its reason. About 80% of physicians believed that they sufficiently provided guidance on target blood pressure to their patients, but only 38% of patients felt their doctors actually did so. This is a simple but critical discrepancy, which doctors should seriously consider. We asked about the important actions required to achieve target blood pressure in the future. Approximately 30% of doctors cited providing a target blood pressure value and its reasons. We must reassess and focus again on guiding patients toward a target blood pressure.

Finally, we understand Japanese doctors want to have more time, opportunities, and better conditions to talk and listen to their patients about hypertension management. Japanese doctors are too busy to complete the process of improvement of hypertension management by themselves. Therefore, multidisciplinary and multilateral cooperation with patients’ families, medical nurses, public health nurses, pharmacists, engineers, office workers, SNS, newspapers, TV and mass media is essential for better management of hypertension.
S-16-2: CLINICAL MANAGEMENT OF MINERALOCORTICOID RECEPTOR-ASSOCIATED HYPERTENSION
Authors: Ichihara Atsuhiro
Published: January 2023

Mineralocorticoid receptor (MR)-associated hypertension is endogenous MR-activated hypertension. Since MR is localized not only in the kidneys and heart but also in vascular smooth muscle cells, adipose tissue, pancreas, and colon, activation of endogenous MR results in severe organ damages through intracellular promotion of inflammation and fibrosis. When primary aldosteronism, which is characterized by endogenous MR activation, is compared with primary hypertension, the risks of arrythmias, cerebrovascular diseases, and cardiovascular diseases are 3 to 5 folds greater in primary aldosteronism than in primary hypertension. This suggests MR activation causes serious outcomes. Thus MR-targeted therapy is needed for achieving healthy longevity. In this presentation, how MR is activated in MR-associated hypertension and effectiveness and safety of a non-steroidal MR blocker esaxerenone will be shown.
S-17-3: ANTIDIABETIC DRUG THERAPY AND SURVIVAL IN ELDERLY FRAIL PATIENTS. REAL-LIFE EVIDENCE FROM ITALY
Authors: Savare Laura , Rea Federico , Valsassina Valeria , Corrao Giovanni , Mancia Giuseppe
Published: January 2023

Objective:

Aim of the study was to evaluate the protective effect of antidiabetic drugs in a large cohort of unselected elderly diabetic patients differing for their clinical status and life expectancy. The evaluation focused, in particular, on a group of patients with a very low survival rate because frail patients are usually excluded from intervention trials, limiting evidence on treatment effectiveness. The protective effect of drug therapy, quantified by the reduction in all-cause mortality with increased adherence to antidiabetic agent therapy, was studied by stratifying patients according to their life expectancy.

Design and method:

The Lombardy (Italy) residents, aged > 65 years, who received > 2 consecutive prescriptions of antidiabetic agents during 2012 were identified and the date of the third prescription was defined as the index date. A case-control study was nested into the cohort of antidiabetic drug users. Death from any cause was the outcome of interest, and cases were cohort members who died during follow-up (up to 2018). For each case, a control was selected and matched for age, gender, and clinical profile. Conditional logistic regression was used to model the risk of outcome associated with four categories of adherence to antidiabetic drugs. Adherence to drug therapy was measured by considering the proportion of days of the follow-up covered by the drugs. The analysis was stratified according to four categories of the clinical profile (good, intermediate, poor, and very poor) differing for life expectancies, as evaluated by a multisource comorbidity score able to accurately predict the risk of death.

Results:

Among the 276,336 patients in treatment with antidiabetic agents during 2012, 188,983 met the inclusion criteria and generated 49,219 deaths during follow-up, 49,201 of whom were matched to a control. The 6-year survival decreased from 85% to 52% from the group of patients with good to the group of patients with a very poor clinical status.

Adherence to treatment was associated with a progressive decrease in the risk of mortality in all categories of clinical status. The reduction from lowest to highest adherence level was 36% (95% CI, 25–46%), 50% (44–56%), 38% (33–42%) and 26% (17–34%) from good to very poor clinical status (Figure).

Conclusions:

In a real-life context, adherence to antidiabetic drugs is associated with a reduction in the risk of mortality regardless of the clinical status of the patients. However, in more frail patients, the benefit of treatment is less than in patients in good clinical condition.
S-17-6: SGLT2 INHIBITION ON VASCULAR FUNCTION AND ATHEROSCLEROSIS: CLEARED OR YET?
Authors: Tanaka Atsushi , Node Koichi
Published: January 2023

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been recently recognized as one of foundational therapies in patients with cardiovascular diseases (CVDs), including heart failure (HF), beyond the use in the diabetes care setting. In particular, SGLT2 inhibitors reduced the risk of HF-related events and cardiovascular death in a broad clinical manifestation of HF, including chronic and even acute HF, regardless of left ventricular ejection fraction. On the other hand, whether treatment with SGLT2 inhibitor can reduce the risk of atherosclerotic CVDs is still uncertain. Moreover, its effects on vascular function and atherosclerosis remain also to be inconclusive. In this talk, we would like to review the effects of SGLT2 inhibition on vascular function and atherosclerosis, based on the recent insights observed in the pragmatic randomized clinical trials, and discuss its role in the cardiovascular care setting.
S-18-5: ENDOTHELIAL GATA5 POSITIVELY REGULATES ANGIOGENESIS VIA CATHEPSIN S-MEDIATED ANGPT2/FLK1 AND MMP2/9 SIGNALING PATHWAYS
Authors: Ren Anmin , Gan Qian , Qu Xinkai
Published: January 2023

Objective:

Although GATA5 is vital in maintaining the function of endothelial cells, the relationship between GATA5 and angiogenesis, however, remains unclear. Our study aims to determine how endothelial GATA5 mediates angiogenesis.

Design and method:

1. C57BL/6 mice were injected with endothelial cell-specific GATA5-overexpressing adeno-associated virus. One week after virus infection, the hindlimb ischemia model was established by ligating the femoral artery of mice, and the blood perfusion ratio of the operated limb/healthy limb was detected by a blood perfusion imager. CD31 staining of mouse gastrocnemius muscle showed the number of new capillaries per unit area. Western Blot and qPCR were used to detect the expression of GATA5 and related angiogenesis factors. 2. On human umbilical vein endothelial cells, transfected lentivirus to knock down the expression of GATA5 and/or administered vascular endothelial growth factor-165 intervention, through CCK-8 experiments were used to detect cell proliferation, scratch experiments to detect cell migration, and endothelial tube formation experiments to detect the ability of cells to form tubes. Western blot and qPCR assays were used to detect the protein and mRNA levels of GATA5, cathepsin S, Angpt2 and Flk1, and MMP2/MMP9. The direct binding of GATA5 to cathepsin S was verified by co-immunoprecipitation experiments. 3. GATA5 knockdown human umbilical vein endothelial cells were transfected with plasmids overexpressing GATA5 or cathepsin S to increase the expression levels of GATA5 or cathepsin S. Cell function and expression of related factors were detected.

Results:

1. The blood perfusion ratio and CD31 immunofluorescence expression of the mice in the endothelium-specific overexpression GATA5 group were significantly higher than those of the negative control mice, and the mRNA and protein levels of angiogenesis factors Angpt2 and Flk1 were increased as well. 2. Cell experiments showed that the knockdown of GATA5 could inhibit cell proliferation, migration and endothelial tube formation stimulated by VEGF-165, and at the same time, reducing the expression of cathepsin S, Angpt2, Flk1 and MMP2/MMP2. Co-immunoprecipitation experiments showed that GATA5 had a direct binding relationship with cathepsin S. 3. Overexpression of GATA5 or cathepsin S reversed the decline in cell migration and tube formation caused by GATA5 knockdown, and up-regulated the expressions of Angpt2/Flk1 and MMP2/MMP9.

Conclusion:

Endothelial GATA5 regulates angiogenesis by regulating endothelial cell proliferation, migration and tube formation through the cathepsin S-Angpt2/Flk1 and MMP2/MMP9 signaling pathways.
S-20-1: ATRIAL FIBRILLATION, ARTERIAL HYPERTENSION AND ALDOSTERONE: THE TRIPLE TROUBLE
Authors: Rossi Gian Paolo
Published: January 2023

With an estimated prevalence of 1–2% in the general population and up to 15% of people over 80 years, atrial fibrillation (AF) is the most common sustained cardiac arrhythmia.

In Europe 4.5- 6.0 million people are estimated to have AF. As two thirds of the AF cases involve patients older than 65 years of age, owing to aging of the population a pandemic of AF is expected to occur over the next decades. This will impose a major burden on all health care systems; moreover, AF increases the risk of heart failure, doubles the risk of death independently of other known predictors of mortality, is the major cause of cardio-embolic stroke and thereby long-term disability. Hence, AF worsens the quality of life and, by causing silent and recurring stroke, leads to cognitive dysfunction and dementia.

Arterial hypertension is the most common cause of nonvalvular AF and is known to anticipate the incidence of AF in susceptible individuals.

A relative or absolute aldosterone excess drives the development of arterial hypertension in many individuals; moreover, in primary aldosteronism, the most common curable cause of arterial hypertension, a 12-fold increase of relative risk of AF, as compared with blood pressure-matched patience with essential hypertension, was documented.

In PAPPHY, a 3-center prospective study, we showed that among 73 the patients who presented with lone AF and arterial hypertension, 42% had primary aldosteronism that was surgically cured in half of them. Moreover, in the PAPY Longitudinal study we showed that AF occurred more commonly at long-term in medically treated than in surgically cured PA patients. These findings are consistent with elegant experimental studies in rodents that documented an increase susceptibility to develop AF with induced hyperaldosteronism. The mechanisms underlying AF in arterial hypertension and hyperaldosteronism will be discussed.
S-21-4: CURRENT REALITIES OF HOME BLOOD PRESSURE MONITORING FROM PHYSICIANS PERSPECTIVES: RESULTS FROM ASIA HBPM SURVEY 2020
Authors: Wang Tzung Dau
Published: January 2023

Background:

Uncontrolled hypertension is a significant problem in many parts of Asia. Effective management is essential to reduce the burden of hypertension. Home blood pressure monitoring (HBPM) is a promising tool that can aid in the diagnosis and management of hypertension. Experts from 11 countries/regions in Asia conceptualized a large-scale survey to examine the current realities of HBPM.

Methods:

A cross-sectional survey was conducted among health care professionals from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam between November 2019 and June 2021. Physicians responses were summarized using descriptive statistics.

Results:

A total of 7,951 physicians participated in the survey. Among all respondents, 50.3% and 33.5% viewed HBPM as highly recognized by physicians and patients in their country/region, respectively. Lack of understanding of HBPM and concern with the accuracy and reliability of HBPM devices were identified as key barriers to HBPM recognition. Nearly all physicians (95.9%) reported recommending HBPM to their patients; however, they reported less than 50% of their patients measured home blood pressure (HBP). Among physicians who recommended HBPM, only 22.4% and 54.1% cited HBP diagnostic threshold values and timing of taking antihypertensive drugs that were consistent with available guidelines, respectively.

Conclusions:

The survey reveals that the recognition of HBPM as a valuable tool to diagnose and manage hypertension is suboptimal in most parts of Asia. Despite high recommendation of HBPM to hypertensive patients by physicians, there are considerable discrepancies between guidelines recommendations and practice realities.
S-21-5: COMPARISON OF THIRD-DOSE TRIPLE VERSUS THIRD-DOSE DUAL ANTIHYPERTENSIVE COMBINATION THERAPIES IN PATIENTS WITH ESSENTIAL HYPERTENSION DURING 8-WEEK FOLLOW-UP
Authors: Hong Soon Jun , Rhee Moo Yong , Jeong Myung Ho , Kim Dae Hee , Lim Sang Wook , Park Kyungil , Lee Jin Bae , Sung Ki Chul , Kim Seok Yeon
Published: January 2023

Objective:

We compared efficacy and safety of low-dose triple versus low-dose dual antihypertensive combination therapies in patients with essential hypertension.

Design and method:

This trial was a multicenter, randomized, double-blind, parallel, phase II study. After a 4-week placebo run-in period, 243 patients were randomized to the third -dose triple combination (ALC group, amlodipine 1.67 mg + losartan potassium 16.67 mg + chlorthalidone 4.17 mg), third-dose dual combination (AL group, amlodipine 1.67 mg + losartan potassium 16.67 mg), (LC group, losartan potassium 16.67 mg + chlorthalidone 4.17 mg), or (AC group, amlodipine 1.67 mg + chlorthalidone 4.17 mg) for 8 weeks. The primary outcome was to compare the mean changes in systolic blood pressure (SBP) from baseline to week 8.

Results:

Baseline patient characteristics and blood pressure did not show significant differences among 4 groups. The mean SBP reductions of ALC group, AL group, LC group and AC group were -18.30 ± 13.23, -13.03 ± 13.30, -16.29 ± 12.36, and -13.80 ± 13.21 mmHg at week 8 from baseline, respectively. The ALC group showed significant SBP reductions in comparison to the AL and AC groups at week 4 (p = 0.0097 and p = 0.0179, respectively) and week 8 (p = 0.0170 and p = 0.0357, respectively). The mean diastolic blood pressure (DBP) reduction from baseline was significantly greater in the ALC group when compared to the AL group (-7.93 ± 7.05 and -4.95 ± 7.96 mmHg, respectively, p = 0.0307).

The proportion of responders for SBP was significantly greater in the ALC group (42.6%) compared to the AL (22.0%), LC (23.3%) and AC (27.1%) groups (p = 0.0126, 0.0210 and 0.0445, respectively) at week 4. Furthermore, the proportion of responders for SBP and DBP was significantly greater in the ALC group (59.7%) compared to the AL (39.3%) and AC (42.4%) groups (p = 0.0222 and 0.0491, respectively) at Week 8. Study drug-related adverse reactions were rare and did not show significant differences among 4 study groups.

Conclusions:

Low-dose triple antihypertensive combination therapy when compared to the low-dose dual combination therapies demonstrated early effective BP control without increasing adverse drug reactions in patients with essential hypertension during 8-week follow-up.
S-23-5: TWO-YEAR RESPONSES OF OFFICE AND AMBULATORY BLOOD PRESSURE TO FIRST OCCUPATIONAL LEAD EXPOSURE
Authors: Yu Yu-Ling , Yang Wen-Yi , Thijs Lutgarde , Melgarejo Jesus , Yu Cai-guo , Wei Dong-mei , Wei Fang-fei , Nawrot Tim , Zhang Zhen-Yu , Staessen Jan
Published: January 2023

Lead exposure causing hypertension is the mechanism commonly assumed to set off premature death and cardiovascular complications. However, at current exposure levels in the developed world, the link between hypertension and lead remains unproven. In the Study for Promotion of Health in Recycling Lead (NCT02243904), we recorded the 2 year responses of office blood pressure (OBP, average of five consecutive readings) and 24 h ambulatory blood pressure (ABP) to first occupational lead exposure in workers newly employed at lead recycling plants. Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 μg/dL). Hypertension was defined according to the 2017 ACC/AHA guideline. Statistical methods included multivariable-adjusted mixed models with participants modelled as a random effect and interval-censored Cox regression. OBP was measured in 267 participants (11.6% women, mean age at enrollment, 28.6 years) and ABP in 137 at two follow-up visits. Geometric means were 4.09 μg/dL for baseline BL and 3.30 for the last-follow-up-to-baseline BL ratio. Fully adjusted changes in systolic/diastolic blood pressure associated with a doubling of the BL ratio were 0.36/0.28 mm Hg (95% confidence interval, 0.55 to 1.27/ 0.48 to 1.04 mm Hg) for OBP and 0.18/0.11 mm Hg (2.09 to 1.74/ 1.05 to 1.27 mm Hg) for 24 h ABP. The adjusted hazard ratios of moving up across hypertension categories for a doubling in blood lead were 1.13 (0.93–1.38) and 0.84 (0.57–1.22) for OBP and ABP, respectively. In conclusion, the 2 year blood pressure responses and incident hypertension were not associated with the BL increase on first occupational exposure.
S-24-4: SIGNIFICANCE OF THE JAPAN MEDICAL ASSOCIATION DATABASE OF CLINICAL MEDICINE (J-DOME) IN THE TREATMENT OF HYPERTENSION IN JAPAN
Authors: Katsuya Tomohiro
Published: January 2023

The Japan medical association Database Of clinical MEdicine (J-DOME) was started with the aim of understanding the actual status of real-world diabetes care at the general practitioner level. The Japan Society of Hypertension and the Japan Medical Association have signed an agreement to register hypertension cases in addition to diabetes cases. Hypertension in Japan is a national disease with an estimated 43 million patients. While the average blood pressure is gradually decreasing, and only 27% of patients achieve their antihypertensive goals, a situation also known as the Hypertension Paradox continues. Although the majority of hypertension care in Japan is provided by general practitioners, information on hypertension care to date has been limited to large-scale studies and epidemiological studies conducted mainly at university hospitals and core hospitals, and the information collected by J-DOME is expected to be important in reflecting real-world blood pressure control, antihypertensive drug use, frequency of complications, etc. The information collected by J-DOME is expected to be important in reflecting real-world blood pressure control, antihypertensive drug use, and frequency of complications.

J-DOME registers three types of cases: hypertension alone, diabetes alone, and combined hypertension and diabetes, and also allows comparison between specialists and non-specialists, so it is possible to understand what specific cases hypertension specialists are treating, from medication use to control status. In fact, hypertension specialists administer more types of antihypertensive medications to cases with slightly elevated blood pressure, with the result that they achieved the target of blood pressure. In addition, some information on daily salt intake estimated from urinary Na and Cr levels is also collected, which provides valuable information on the average salt intake.

The Japan Society of Hypertension has spontaneously established an organization called the Practitioner Subcommittee, which has formed a working group and is conducting various promotional activities to increase the number of cases in conjunction with the society's task force. Specifically, the subcommittee has been promoting J-DOME at various lecture meetings, and reaching out to local medical associations, in order to increase case registration throughout Japan. At this meeting, we would like to discuss the significance of hypertension case registration in J-DOME from various angles, taking into account the contents of the third report published in August 2021.
S-26-1: LESSONS LEARNED ABOUT HYPERTENSION FROM RENAL DENERVATION CLINICAL TRIALS
Authors: Weber Michael
Published: January 2023

Renal denervation is being studied in clinical trials at a time when the community management of hypertension has fallen behind expectations. A major issue is poor adherence to medications. The DENER HTN trial of denervation used urine/plasma medication monitoring to confirm patient drug taking, but discovered that despite rigorous instructions to patients only 50% were taking drugs as prescribed, and 20% were taking no drugs at all. Similarly, the Spyral On Meds trial reported that only about 50% of patients took their medications consistently during the trial. But clinicians are also part of the problem: despite unrestricted access to drugs, long term follow-up of non-denervated patients in RDN trials has failed to achieve acceptable levels of BP control. On a positive note, the TRIO RDN trial in patients with uncontrolled hypertension despite multi-drug regimens observed that substitution by a single-pill 3-drug combination was remarkably effective in many patients. Guidelines recommend out-of-office BP measurements, and home BP is now used by many patients and is helpful in diagnosing hypertension. But HBP may be a two-edged sword. In the REQUIRE RDN trial, where patients routinely measured HBPs, an early significant BP-reduction advantage to RDN over sham progressively disappeared as some patients with lower BPs (mainly RDN patients) started reducing medications, and those with higher BPs (mainly sham) increased medications. Ambulatory BP monitoring is also recommended. Its data are reproducible over time for cohorts, but the Spyral Off-Meds trial demonstrated large fluctuations of BP, both upwards and downwards, in individuals in the control group, thus questioning the value of single ABPM procedures for diagnosing hypertension in clinical practice. Surveys of hypertensive patients attitudes regarding RDN in Japan and the United States have demonstrated a likely acceptance if it is needed to improve BP control. Interestingly, this occurred in patients who in many cases were not adherent to medications; but yet were concerned at the possible serious medical consequences of poorly controlled BP, thus illustrating a challenging clinical paradox. An important lesson from these observations in RDN studies is that there are limits to what can be achieved with conventional drug therapy in many people with hypertension, and that the clinical use of RDN may not just be appropriate for patients with true resistant hypertension, but might be of particular value in those who despite the well-intentioned prescription of medications remain with unacceptably high blood pressures.
S-27-4: OXIDIZED LDL POTENTIATES ANGIOTENSIN II-INDUCED GALPHAQ ACTIVATION THROUGH THE AT1-LOX1 RECEPTOR COMPLEX IN KIDNEY CELLS
Authors: Huang Yibin , Yamamoto Koichi , Takahashi Toshimasa , Ihara Jittoku , Nozato Yoichi , Rakugi Hiromi
Published: January 2023

Objective:

We have reported that the binding of oxidized LDL (oxLDL) to its receptor, LOX-1 activates the G protein-coupled angiotensin II(AII) type 1 receptor (AT1) through membrane complex of the receptors. oxLDL-induced activation of AT1 is characterized by the beta-arrestin-biased signaling with no activation of Galphaq, the main effector of AII-induced cellular response (2021 iScience). In this study, we performed cell experiments to investigate how the co-treatment of oxLDL and AII activates AT1 particularly by focusing on Galphaq-dependent pathway.

Design and Methods:

We used CHO-cells stably transfected with AT1 (CHO-AT1), LOX-1 and AT1 (CHO-LOX-1-AT1) and two rat kidney cells (NRK49F and NRK52E). Activation of Galphaq and the subsequent induction of Ca influx were quantified by accumulation of IP1 and Fura-2 AM assay, respectively. We also utilized Galphaq-BRET biosensor vector to detect the activity of Galphaq. We assessed mRNA expression of genes associated with oxidative stress, inflammation, and fibrosis in NRK49F and NRK52E. We also assessed protein expression of alphaSMA as a molecular marker of epithelial mesanchymal transition (EMT) after 3 days of the indicated stimulation in NRK49F and NRK52E.The proliferative activity was measured using BrdU assay in NRK49F.

Results:

The activation of Galphaq was not observed by oxLDL treatment alone but was enhanced by the co-treatment of oxLDL and AII compared to AII alone in CHO-LOX-1-AT1 but not in CHO-AT1. Ca influx was induced not by oxLDL alone but by the co-treatment of oxLDL and a low concentration of AII that was insufficient to induce Ca influx when treated alone in CHO-LOX-1-AT1. We also found that the activation of Galphaq and the induction of Ca influx were detected by the co-treatment of oxLDL and AII but not by single treatment in rat kidney cells. These phenomenons were inhibited by ARB, a Gq inhibitor or the siRNA knockdown of AT1 or LOX-1. Furthermore, combination treatment enhanced the expression of the majority of genes associated with renal injury compared to the single treatment, and EMT was induced only by the combination treatment. These phenomenons were inhibited either by ARB or the Gq inhibitor. The combination treatment enhanced the proliferative activity of kidney fibroblasts compared with single treatment, that was inhibited by ARB, the Gq inhibitor or the siRNA knockdown of AT1 or LOX-1.

Conclusions:

These findings suggest the synergistic role of the AT1-LOX-1 interaction whereby oxLDL potentiates Ang II-induced Galphaq signaling, leading to the enhancement of renal injury-associated cellular response.
S-28-6: URINARY METABOLOMICS, DIETARY SALT INTAKE AND BLOOD PRESSURE: THE AFRICAN-PREDICT STUDY
Authors: Strauss-Kruger Michél , Zyl Tertia van , Pieters Marlien , Kruger Ruan , Mokwatsi Gontse , Gafane-Matemane Lebo , Mbongwa Hlengiwe , Jacobs Adriaan , Schutte Aletta Elisabeth , Louw Roan , Mels Carina
Published: January 2023

Objective:

Excessive salt intake is the leading dietary risk factor for cardiovascular disease (CVD). This increased risk may be attributed to alterations in the human metabolome. Salt sensitivity is associated with ethnicity, and ethnic differences in the interaction between sodium intake and the metabolome may play an integral part in CVD development. We therefore investigated 1) the urinary metabolomic profiles of Black and White adults according to low, moderate and high dietary salt intake; and 2) explored the relationships of identified metabolites with blood pressure.

Design and Methods:

This study included data of White (N = 447) and Black (N = 380) adults aged 20 to 30 years from the African-PREDICT study. Estimated salt intake was determined from 24hr urinary sodium. Urinary amino acids and acylcarnitines were measured using liquid chromatography tandem mass spectrometry. Clinic, 24hr and central systolic blood pressure (SBP) were measured.

Results:

Whites with a high salt intake (> 10 g/day) had higher SBP (clinic, 24hr and central) compared to those with low (< 5 g/day) or moderate (5 to 10 g/day) salt intakes (all p < 0.05). The metabolites GABA (q = 0.020), citrulline (q = 0.020), glutamic acid (q = 0.046), serine (q = 0.054) and proline (q = 0.054) were lower in those with higher salt intake. In stepwise multivariable adjusted regression analyses, we found that clinic SBP of white adults were inversely associated with GABA (Adj. R2 = 0.35; Std. β=-0.123; p = 0.005), serine (Adj. R2 = 0.35; Std. β=-0.099; p = 0.022) and proline (Adj. R2 = 0.35; Std. β=-0.099; p = 0.021), and central SBP with GABA (Adj. R2 = 0.34; Std. β=-0.094; p = 0.036), glutamic acid (Adj. R2 = 0.34; Std. β=-0.090; p = 0.035) and proline (Adj. R2 = 0.034; Std. β=-0.106; p = 0.015). In Black adults, there were no differences in SBP or metabolites between low, moderate or high salt intake groups, with no relationships between SBP and GABA, glutamic acid, citrulline, serine or proline.

Conclusion:

In White adults, high salt intake was associated with low levels of GABA, glutamic acid, serine and proline, which in turn were related to high SBP. We hypothesise that metabolomic changes are related to salt intake and may contribute to pathophysiological mechanisms associated with increased blood pressure.
S-30-4: SEX DIFFERENCES IN IMPACT OF CUMULATIVE SYSTOLIC BLOOD PRESSURE FROM CHILDHOOD TO ADULTHOOD ON ALBUMINURIA: A 30-YEAR PROSPECTIVE COHORT STUDY
Authors: Wang Dan , Mu Jianjun
Published: January 2023

Background and Objectives:

Albuminuria is recognized as being a predictor of cardiovascular and renal disease. The aim of this study was to identify the impact of the long-term burden and trends of systolic blood pressure on albuminuria in midlife, as well as to explore sex differences concerning this relationship.

Methods:

This longitudinal study consisted of 1,683 adults aged 6–15 years who had been examined 4 or more times for blood pressure starting in childhood, with a follow-up time period of 30 years. The cumulative effect and longitudinal trend of blood pressure were identified by using the area under the curve (AUC) of individual systolic blood pressure measurement with a growth curve random effects model. Albuminuria was defined as a urine albumin-to-creatinine ratio (uACR)¡Ù30 mg/g.

Results:

Over 30 years of follow-up, 190 people developed albuminuria, including 53.2% males and 46.8% females. The uACR values increased as the total and incremental AUC values increased. Additionally, women had a higher albuminuria incidence in the higher SBP AUC groups than men do (13.3% for men vs. 33.7% for women). Logistic regression showed that the ORs of albuminuria for males and females in the high group were 1.34 (0.70–2.60) and 2.94 (1.50–5.74), respectively, after adjustments. Similar associations were found in the incremental AUC groups. Moreover, there was a significant interaction between AUC groups and sex on the outcomes of albuminuria.

Conclusions:

The presence of higher cumulative SBP was correlated with higher uACR levels and a risk of albuminuria in middle age, especially in women. The identification and control of cumulative SBP levels from an early age may assist in reducing the incidences of renal and cardiovascular disease for individuals in later life.
S-34-1: CENTRAL HYPERTENSION IS A NON-NEGLIGIBLE CARDIOVASCULAR RISK FACTOR
Authors: Li Yan
Published: January 2023

High blood pressure (BP) confers cardiovascular risk. However, the clinical value of central BP remains debatable. Central and brachial BPs are closely correlated. In most prospective investigations, elevated central and peripheral BPs were similarly associated with adverse outcomes. Outcome-driven thresholds of the central systolic BP estimated by the type I device were on average 10 mmHg lower than their brachial counterparts. Cross-classification based on the central and brachial BPs identified that nearly 10% of patients had discrepancy in their status of central and brachial hypertension. Irrespective of the brachial BP status, central hypertension was associated with increased cardiovascular risk, highlighting the importance of central BP assessment in the management of hypertensive patients. Newer antihypertensive agents, including renin-angiotensin-aldosterone system inhibitors and calcium channel blockers, were more efficacious than older agents in central BP reduction. Clinical trials are warranted to demonstrate whether controlling central hypertension with an optimized antihypertensive drug treatment will be beneficial beyond the control of brachial hypertension.
S-36-1: TYPE OF EXERCISE AND ARTERIAL STIFFNESS
Authors: Miyachi Motohiko
Published: January 2023

Arterial stiffness increases with age and is an independent risk factor for death from future cardiovascular diseases. Habitual exercise has been recommended as one of the effective treatments and prevention for hypertension and cardiovascular diseases. In this presentation, I would like to introduce the results of research on the effects of different types of exercise on arterial stiffness.

A lot of studies have reported that habitually moderate- to vigorous- intensity aerobic exercise, e.g., walking, running, and swimming reduces arterial stiffness, especially in middle-aged and elderly. Our study also reveals that arterial stiffness is lower in elderly with more light-intensity physical activity and less sedentary behavior. Surprisingly, bodybuilders and American football players who do a lot of strength training recommended along with aerobic exercise have higher arterial stiffness and blood pressure than sedentary peers. We have reported for the first time that several months of high-intensity strength training in young subjects have the unfavorable effect of increasing arterial stiffness. On the other hand, systematic review and meta-analysis also suggests that moderate-intensity strength training in middle-aged and elderly with increased arterial stiffness has less adverse effects. Strength and aerobic combined exercise suppress the increase in arterial stiffness. In addition, we found that the arteries were stiff in middle-aged and elderly with lower whole-body flexibility. It has also been reported that several months of yoga and stretching interventions reduce arterial stiffness.

Since the effect on arterial stiffness differs depending on the type of exercise, it is necessary to carefully select the exercise type when using exercise for treatment of hypertension. The mechanism of changes in arterial stiffness due to exercise has not been fully elucidated. Further research is needed to provide more reliable exercise prescription for hypertension.
S-36-2: SOCIAL FRAMEWORK TO PROMOTE SALT REDUCTION AND HEALTHY DIETS WITHIN HYPERTENSION AND STROKE PREVENTION
Authors: Polonia Jorge
Published: January 2023

Beyond the physiological effects of sodium and potassium strong evidence from animal, clinical and epidemiological studies, has implicated excess dietary sodium and low potassium intake as major factors associated with the development of hypertension and increase in stroke risk. Daily salt intake of 5–6 g 85–100 mmol was recommended for the general population i.e. 2.0–2.4 g Na along with K intake to at least 90 mmol d 3.51 g perd. Randomized trials demonstrate that salt reduction and potassium increase in diet lowers blood pressure and reduces the risk of brain damage and cardiovascular disease. Population studies showed that 15 percent reduction of salt intake from 9.5 g/day was associated with a 40 percent reduction of stroke and CHD mortality. Potassium lowers BP via multiple mechanisms, by acting directly on the vasculature and by triggering a signalling cascade mediated by endothelium and also reduces salt-sensitivity. A meta-analysis of 21 RCTs reported that increasing potassium intake lowers BP 3.5/2.0 mm Hg and the risk of stroke. Eating more than 11 g of salt /day was associated with 2.5 times more likely to have a stroke than those who got less than 4.5 g /day. Switching from regular salt to a salt substitute reduced the risk for stroke, major CV events and death in a large trial of adults in rural China with a history of stroke or high risk for stroke. High salt intake reduces resting cerebral blood flow and induces endothelial dysfunction in mice and impairs vasodilatory responses of cerebral vessels. Gut-brain relation links dietary salt to cognitive impairment though a gut-initiated adaptative immune response damaging brain function via increase in circulating IL-17. A high potassium diet reduces cerebral infact size and improves vascular function independently of BP changes. Thus high salt and low potassium intake interfere in multtiple brain vascular strutural complex processes including fluid homeostasis and inflammatory mechanisms, immune responses and gut-microbiome-brain axis.
S-38-4: ASSOCIATION BETWEEN DNA METHYLATION AGE OR DNA DAMAGE IN URINARY SHEDDING CELLS AND EARLY CKD
Authors: Hishikawa Akihito , Hayashi Kaori , Sugita Erina , Yoshimoto Norifumi , Nakamichi Ran , Yoshida Eriko , Shimizu Ryoko , Takaishi Hiromasa , Itoh Hiroshi
Published: January 2023

Objective:

Recent studies have identified that aggregate DNA methylation status of specific sites measures biological age, referred to as the DNA methylation clock. However, the relationship between kidney diseases and DNA methylation clock has been unclear. In this study, we aimed to investigate the association between DNA methylation age or DNA damage in urinary shedding cells and early CKD.

Design and method:

Individuals aged 45–81 years old, who visited Keio University Hospital for annual health check-up were enrolled. A total of 22 participants (14 males, 8 females) aged 61.6 ± 10.0 years old were eligible for this study. We evaluated a 71 CpG epigenetic age predictor, referred to as the Hannum's clock, which lacks 6 probes on the EPIC array using blood samples from the patient. 50 ml of urine samples were collected and centrifuged, and mRNA was extracted to analyze the expression of phenotypical markers and epigenetic modulators in urine derived cells by quantitative RT–PCR method as previously described. DNA was also extracted from urine derived cells, and DNA double strand breaks (DSBs) were evaluated by the quantitative long distance PCR method as previously described (Hishikawa, et al. Sci rep 2020). The association between biological aging (Hannum's clock age − chronological age) and clinical data was investigated.

Results:

Hannum's clock correlated with chronological age, and biological aging (Hannum's clock age − chronological age) was promoted in CKD patients (eGFR 43–59). DNA DSBs of the nephrin gene was also promoted in CKD patients. DNMT3 expression in urinary shedding cells correlated with biological aging.

Conclusions:

To our knowledge, this is the first study to demonstrate the possible association of biological aging measured by DNA methylation clock and CKD, especially in early stage. Podocyte DNA DSBs and urine DMNT3 expression may be a potential marker of biological aging.