bluuebunny/crossref_metadata_2025_split huggingface dataset:
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-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-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-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-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.