bluuebunny/crossref_metadata_2025_split huggingface dataset:
S-37-3: NIGHTTIME AND DAYTIME HOME BLOOD PRESSURE AND THE CARDIOVASCULAR DISEASE INCIDENCE IN TREATMENT-RESISTANT HYPERTENSION
Authors: Narita Keisuke , Hoshide Satoshi , Kario Kazuomi 
Published: January 2023

Introduction:
Individuals with treatment-resistant hypertension (TRH) often concurrently have obesity, diabetes, or sleep apnea, conditions that confer a high risk of cardiovascular disease (CVD) and are related to nocturnal hypertension. We therefore hypothesized that nighttime home BP may be a superior predictor of CVD events compared to daytime home BP in patients with TRH.

Methods:
We conducted the present study of 297 patients with TRH, which was defined as uncontrolled office BP (≧140/90 mmHg) with using three classes of medications including diuretics or using ≧4 classes of medications with controlled or uncontrolled BP levels. The patients were among the original 2,545 outpatients in the J-HOP (Japan Morning Surge-Home Blood Pressure) Nocturnal BP study, a nationwide practitioner-based study of nighttime home BP monitoring (HBPM), and underwent consecutive 14-day daytime (morning and evening) HBPM and nighttime HBPM using a device programmed to take nighttime BP measurements at 2:00, 3:00, and 4:00 a.m. (one measurement at each time point, for a total of three readings). The primary CVD outcome during the follow-up period was defined as the development of coronary artery disease, stroke, aortic dissection, or heart failure hospitalization.

Result:
The mean age of the 297 patients was 65.2 ± 10.5 years; 50.8% were male, and the mean number of antihypertensive medication classes was 3.6 ± 0.6. During a mean follow-up of 6.5 years, 41 CVD events occurred. The primary CVD outcome occurred more frequently in the group of patients with both uncontrolled nighttime home BP (≧120/70 mmHg) and uncontrolled daytime home BP (≧135/85 mmHg) (Figure). The model performance assessed by the C-statistic tended to be improved by adding nighttime home SBP to the base model including confounding factors and office SBP (C-statistic [95%CI], 0.712 [0.652, 0.830] to 0.748 [0.686, 0.851], P = 0.078) and to the model that included the base model and daytime home SBP (C-statistic, 0.714 [0.660, 0.835] to 0.747 [0.702, 0.857], P = 0.065). Adding daytime home SBP did not improve the performance of the base model (C-statistic, 0.712 [0.652, 0.830] to 0.714 [0.660, 0.835], P = 0.872).

Conclusion:
Our results indicate that nighttime BP measured by the home BP device was associated with an increased risk of CVD events even after adjustment for the daytime home BP level in patients with TRH.
S-38-9: DNA DAMAGE REPAIR AND DNA METHYLATION IN THE KIDNEY AND CKD
Authors: Hayashi Kaori , Itoh Hiroshi 
Published: January 2023

In recent years, the results of large clinical trials have suggested that transient treatment for lifestyle-related diseases has sustained effects on prevention for cardiovascular complication over a long period of time, which has been noted as “memory effect’’. One of the possible mechanisms of the memory effect is epigenetic changes. Epigenetic alterations have sustained effects on gene expressions, which contribute to the pathogenesis of chronic diseases, including kidney diseases.
DNA damage repair is one of the chances to re-write the epigenetic marks, and continuous DNA damage may cause accumulation of epigenetic changes. We have demonstrated the importance of DNA damage repair in the kidney and its relations to kidney diseases through DNA methylation changes. The DNA repair system is strikingly cell-type specific, depending on the expression of DNA repair factors; therefore, different DNA repair systems may exist in each type of kidney cell. In this talk, I would like to focus on DNA damage repair in podocytes and proximal tubular epithelial cells, and discuss the possibility as a prognostic marker and a therapeutic target. Investigations of DNA damage repair and epigenetic changes in the kidneys may achieve a profound understanding of kidney aging and diseases.
S-39-1: COVID-19 AND HYPERTENSION IN JAPAN, AND KANAGAWA RASI COVID-19 STUDY
Authors: Tamura Kouichi , Matsuzawa Yasushi , Kobayashi Kazuo 
Published: January 2023

Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) caused a global coronavirus disease-2019 (COVID19) pandemic, as declared by the World Health Organization on March 11, 2020. COVID19 was confirmed for the first time in January 2020, and despite epidemic prevention efforts, the number of patients with COVID19 continued to increase, primarily in metropolitan areas. To prevent the further spread of COVID19, the Japanese government announced a state of emergency on 7 April 2020, similar to the lockdowns impleme	nted in other countries. We showed a significant increase in office BP with the white coat phenomenon was observed during the state of emergency, as well as an increase in related stress, thereby indicating that we should pay more attention to BP management during stressful global events, including the COVID19 pandemic, to prevent cardiovascular events (Kobayashi K, et al. Hypertens Res 2022; Kobayashi K, et al. Ito S, et al. J Diabetes Investig Apr 18 Epub, 2022). In addition, since the onset of the COVID19 pandemic, the possible roles of renin angiotensin system (RAS) inhibitors in COVID19 have been debated as favorable, harmful, or neutral. ACE2 not only is the entry route of SARSCoV2 infection but also triggers a major mechanism of COVID19 aggravation by promoting tissue RAS dysregulation, which induces a hyperinflammatory state in several organs, leading to lung injury, hematological alterations, and immunological dysregulation. ACE inhibitors and ARBs inhibit the detrimental hyperactivation of the RAS by SARSCoV2 and increase the expression of ACE2, which is a counterregulator of the RAS. Several studies have investigated the beneficial profile of RAS inhibitors in COVID19; however, this finding remains unclear. Further prospective studies are warranted to confirm the role of RAS inhibitors in COVID19 (Matsuzawa Y, et al. Hypertens Res 2020; Matsuzawa Y, et al. Hypertens Res, 202; Sato R, et al. Clin Exp Nephrol 2022).
S-39-3: ENDOTHELIAL INFLAMMATION AND DYSFUNCTION INDUCED BY SARS-COV-2 SPIKE PROTEIN 1 INVOLVE ADAM17 AND INTERFERON ACTIVATION PATHWAYS
Authors: Rios Francisco J , Montezano Augusto C , Camargo Livia L , Lopes Rheure A , Redondo Ana B Garcia , Cortes Eliju Aranday , Briones Ana M , McLauchlan John , Touyz Rhian M 
Published: January 2023

Objective:
COVID19 is associated with vascular inflammation. IFN-alpha (IFNα) and IFN-lambda3 (IFNλ3) are potent cytokines produced in viral infections. Their effects involve interferon-stimulated genes (ISGs) and may influence expression of angiotensin-converting enzyme 2 (ACE2), the receptor for S-protein (S1P) of SARS-CoV-2. We hypothesized that S1P-induced immune/inflammatory responses in endothelial cells (EC) are mediated via IFN-activated pathways

Design and methods:
Human ECs were stimulated with S1P (1 μg/mL), IFNα (100ng/mL) or IFNλ3 (100IU/mL). Because ACE2, ADAM17 and TMPRSS2 are important for SARS-CoV-2 infection, we used inhibitors of ADAM17 (marimastat, 3.8 nM), ACE2 (MLN4760, 440pM), and TMPRSS2 (camostat, 50 μM). Gene and protein expression was investigated by real-time PCR and immunoblotting, respectively. Vascular function was assessed in mesenteric arteries from wild-type (WT) normotensive and hypertensive (LinA3) mice and in ISG15-deficient (ISG15KO) mice.

Results:
S1P increased expression of IFNα (3-fold), IFNλ3 (4-fold) and ISGs (2-fold) in EC (p < 0.05). EC responses to IFNα (ISG15: 16-fold) were greater than to IFNλ3 (ISG15: 1.7-fold) (p < 0.05). S1P increased gene expression of IL-6 (1.3-fold), TNFα (6.2-fold) and IL-1β (3.3-fold), effects that were amplified by IFNs. Only the ADAM17 inhibitor marimastat inhibited S1P effects. IFNα and IFNλ3 increase protein expression of ADAM17 (27%) and TMPRSS2 (38%). No changes were observed on ACE2 expression. This was associated with increased phosphorylation of Stat1 (134%), Stat2 (102%), ERK1/2 (42%). EC production of IL-6 was increased by IFNα (1,230pg/mL) and IFNλ3 (1,124pg/mL) vs control (591pg/mL). Nitric oxide generation and eNOS phosphorylation (Ser1177) were reduced by IFNα (40%) and IFNλ3 (40%). Vascular functional responses demonstrated that endothelium-dependent vasorelaxation (% Emax) in vessels from WT-mice stimulated with IFNα (67%) and IFNλ3 (71%) were reduced vs control (82%) (p < 0.05). Responses were not altered in vessels from ISG15KO mice. Increased contraction was observed only in vessels from hypertensive mice treated with IFNα (9.1 ± 0.5mN vs control: 7.3 ± 0.3mN) (p < 0.05).

Conclusions:
In ECs, S1P, IFNα and IFNλ3 increased ISG15 and IL-6 by mechanisms dependent on ADAM17. IFNs amplifies endothelial cell inflammatory responses and induced vascular dysfunction through ISG15-dependent mechanisms, with augmented effects in hypertension. Our findings demonstrate that S1P induces immune/inflammatory responses that may be important in endotheliitis associated with COVID-19. This may be especially important in the presence of cardiovascular risk factors, including hypertension.
S-40-3: MEMORY GAMMA DELTA T CELLS PLAY A ROLE IN HYPERTENSION
Authors: Paradis Pierre , Comeau Kevin , Schiffrin Ernesto L 
Published: January 2023

Objectives:
A subset of T cells, γδ T cells, participate in the pathogenesis of hypertension. It has been shown that memory T cells develop after a hypertensive insult and sensitize mice to develop hypertension to subsequent mild hypertensive stimuli. However, whether memory γδ T cells develop and play a role in hypertension is unknown. We hypothesize that memory γδ T cells form after a hypertensive challenge, and that they sensitize mice to develop hypertension to mild hypertensive stimuli.

Methods:
Ten-12-week-old C57BL/6J mice were exposed or not to a pressor dose of angiotensin II (490 ng/kg/min, SC) for two weeks, followed by a two-week washout period, and then infused with a subpressor dose of angiotensin II (140 ng/kg/min, SC) for two weeks. Blood pressure (BP) was measured by telemetry and memory γδ T cells profiled by flow cytometry. A subset of mice was injected IP with 400 μg of anti-T cell receptor γδ-depleting or isotype control antibodies 1 day before and 6 days after the initiation of second hypertensive challenge. A final subset was injected IV with 2.5x105 γδ T cells isolated from hypertensive or normotensive mice, and then exposed to a subpressor dose of angiotensin II as above.

Results:
Repeated hypertensive challenges yielded a higher systolic BP than one mild hypertensive stimulus (154 ± 4 vs 120 ± 3 mm Hg, P < 0.01). Two-week pressor dose angiotensin II increased effector memory γδ T cells in mesenteric artery perivascular adipose tissue (1.25 ± 0.37% vs. 0.24 ± 0.12%, P < 0.05) and mesenteric lymph nodes (1.49 ± 0.03% vs 0.82 ± 0.15%, P < 0.05). γδ T cell depletion reduced systolic BP elevation from day 8 (135 ± 5 vs 150 ± 5 mm Hg, P < 0.05) to day 13 of the second hypertensive challenge (150 ± 5 vs 163 ± 2 mm Hg, P < 0.05). Adoptive transfer of γδ T cells isolated from hypertensive compared to normotensive mice caused a greater systolic BP elevation in response to a subpressor dose of angiotensin II (159 ± 3 vs 142 ± 6 mm Hg, P < 0.01).

Conclusion:
Memory γδ T cells develop after a hypertensive challenge and sensitize mice to mild hypertensive stimuli. Memory γδ T cells may represent a novel therapeutic target to treat hypertensive humans.
S-40-5: ROLE OF INTERFERON GAMMA IN T CELL MEDIATED SALT-RETENTION IN THE KIDNEY AND PROGRESSION OF HYPERTENSION
Authors: Benson Lance N , Liu Yunmeng , Guo Yunping , Xiong Yunzhao , Deck Katherine , Mora Christoph , Mu Shengyu 
Published: January 2023

Objective:
In accordance with previous studies implicating the immune system in the development of hypertension, we found that CD8+ T cells (CD8Ts) infiltrate the kidneys and stimulate distal convoluted tubular cells (DCTs), to upregulate sodium-chloride co-transporter (NCC) activity, leading to excessive salt retention. However, the precise molecules driving this direct interaction between CD8Ts and DCTs have not yet been identified. Here we hypothesize that gamma interferon (IFNg), released by activated CD8Ts, primes the tubular cell to promote interactions between activated CD8Ts and DCTs during the development of salt-sensitive hypertension. We predict blocking this molecular pathway will reduce CD8T-homing into the kidney, lowering blood pressure.

Design & Method:
In co-culture of mouse CD8Ts and DCTs, recombinant mIFNg, IFNg-neutralizing antibody, and specific siRNAs against the IFNg-receptor or PDL1 were used to determine the role of IFNg-PDL1 pathway in the CD8T-DCT interaction. To validate these studies, we employed IFNg knockout (KO) mice, mice with systemically blocked PDL1 using anti-PDL1 antibody or with renal tubule-specific knockdown of PDL1 (mediated via nanoparticles) in the DOCA-salt model and the CD8T adoptive transfer hypertension models. Blood pressure was monitored using radio-biotelemetry. Endpoint analysis involved flow cytometry, RT-qPCR, and western blot, and immunohistochemistry.

Results:
We found that CD8Ts isolated from DOCA-salt treated hypertensive mice produce more IFNg and exhibit augmented ability to interact with DCTs compared to those from sham normotensive mice. IFNg stimulation to mDCTs increased expression of CD8-specific antigen presenting molecule MHC-I and CD8T-co-signaling molecule PDL1, which enhanced the interaction between CD8Ts and DCTs, consequently upregulating NCC expression in DCTs, leading to enhanced salt retention. These effects on MHC-I, PDL1, or NCC expression were abolished by neutralizing IFNg in co-culture of DCTs and activated CD8Ts, and knockdown of PDL1 in DCTs blunted NCC expression and sodium retention. In-vivo results verified the in-vitro studies. We found that in both IFNg-KO mice and WT mice receiving PDL1-antagonizing antibodies, DOCA-salt treatment failed to elevate their blood pressure and reduced T cell infiltration and NCC expression within their kidneys compared to WT mice receiving the same treatment (anti-PDL1 results shown in Figure 1). Similar results were observed in DOCA-salt treated mice with renal tubule-specific knockdown of PDL1.

Conclusion:
In salt-sensitive hypertension, activated CD8Ts demonstrate enhanced ability to interact with DCTs leading to increased expression of NCC and sodium retention through a IFNg-PDL1 pathway mediated mechanism. Blocking the IFNg-PDL1 pathway prevents CD8T-DCT interaction both in vitro and in vivo, ameliorating hypertension.
S-42-6: COVID-19 MORTALITY CORRELATES WITH CHRONIC DISEASE BURDEN AMONG COUNTRIES’ ONGOING SOCIAL DEVELOPMENT
Authors: Araki Shuichiro 
Published: January 2023

Background:
The COVID-19 death rate has varied by country. Although studies have suggested some biomedical risk factors including hypertension, social factors may not yet be explored enough to prepare for the next pandemic, which might include health policies such as the role of achievement of universal health coverage (UHC). In this study, global data were probed from an ecological perspective.

Methods:
COVID-19 pandemic-relevant data were obtained from websites provided by WHO, UN, and academic society. The outcome variable was defined as annual COVID-19 deaths per 100,000 population in 2020 and 2021. The chronic disease mortality defined by addition of mortalities from cardiovascular diseases and neoplasms in 2019 in the same unit as the outcome variable, and Socio-Demographic Index (SDI), a new metric for social development created by Global Burden of Disease Study were used for main variables. Also, non-communicable disease risk factors and social factors including the UHC service coverage index were for independent variables. Countries which had elderly population (age > = 65 y.o.) over seven per cent and between middle and high SDI quintiles (divisions by SDI) were included for analyses.

Results:
The COVID-19 mortality was significantly higher in 2021 than in 2020, particularly in high-middle SDI quintile countries. A multiple regression model suggested that the preceding chronic disease mortality positively correlated to the COVID-19 mortality, in contrast to a negative correlation of SDI (Table 1). By multiple logistic regression models using dummy variables for the three-quantile groups of the SDI-to-mortality negative slope coefficient levels as an indicator of social disparity, i.e., Mild Medium and Steep, respectively, aging (elderlies’ proportion), raised blood pressure prevalence (SBP > = 140 and/or DBP > = 90 mmHg), obesity prevalence (BMI > = 30 kg/m2), current tobacco use, and alcohol consumption per capita had a positive correlation as a way of slope gradient order. On the other hand, among risk factors, diabetes prevalence had a negative correlation to Steep. With data from a systematic review, angiotensin converting enzyme 1 homozygote insertion (II) polymorphism prevalence was correlated with Mild. The UHC service coverage index had a significant protective correlation.

Conclusion:
Taken together, the disparity in the chronic disease burden was a culprit for the impact of the pandemic, especially among countries in the middle of transition to advanced society, represented by middle and high-middle SDI. Therefore, accelerating primary care system under UHC should offer the key to the alleviated chronic disease burden and the next pandemic preparedness.
S-43-5: A PROSPECTIVE OBSERVATION FOR ORTHOSTATIC DYSREGULATION AND INTOLERANCE IN ADOLESCENCE: STUDY PROTOCOL OF THE SUITA OFFSPRING STUDY
Authors: Kashima Rena , Kokubo Yoshihiro , Arafa Ahmed , Teramoto Masayuki , Nakai Akane , Sakai Yukie , Nosaka Saya , Yasui Yuka , Kogirima Miho , Kato Yoshiaki , Sakata Yasuhiko 
Published: January 2023

Background:
In recent years, the number of adolescents who do not attend school due to orthostatic dysregulation (OD) has increased rapidly in Japan, and countermeasures are urgently needed. In contrast, orthostatic intolerance (OI) is used as its counterpart in Western countries, and no internationally unified disease concept exists. Therefore, it is necessary to compare a population-based prospective study of OD and OI in adolescent urban communities.

Objective:
This study aims to show the clinical characteristics and prognosis of OD and OI in adolescent urban communities.

Methods:
We will launch the offspring cohort in 2022 in two school districts of Suita City, where we encourage medical examinations for all 11-, 14-, and 17-year-old adolescents. Approximately 200 adolescents of each age group will be undergoing medical examinations as research participants. We will perform a medical check-up to detect the constituents of metabolic syndrome, OD, and OI. We will implement questionnaires for the participants based on the Japanese OD Diagnostic and Treatment Guideline (OD symptoms) and diagnostic criteria in Western countries (OI symptoms). If any of the OD or OI symptoms (at least 3 points, 1 point or more) are positive, they will continue with a 10-minute standing test and their parents will fulfill the checklist for diagnosis of OD with psychosomatic disorder based on the aforementioned OD Guideline. Participants who are positive in the standing test will undergo echocardiography, Holter electrocardiography, and Parent-child home blood pressure measurements. We will refer to the Maternal and Child Health Handbook, Infant Health Examination, School Health Examination, and Lifestyle Related Disease Prevention Health Examination to explore OD and OI risk factors (for example, rapid change in growth curve and circadian rhythm formation). We will compare the prevalence of OD and OI by category using the respective diagnostic criteria in Japan and Western countries and reveal the relationship with classical risk, the diurnal variation in HBP of participants and their parents, cardiac function, and autonomic function. We will conduct follow-up studies every 3-year until 20 years old to examine morbidity and prognosis. In addition, we will perform a selected lifestyle questionnaire focusing on diet and physical activity for adolescents and then use metabolomic analysis to compare plasma metabolite profiles of with and without OD and OI participants to detect modifiable risk factors targeted in future interventions.
S-44-3: GENDER DIFFERENCE IN THE ASSOCIATION OF DIETARY CALCIUM INTAKE WITH BLOOD PRESSURE: ANALYSIS OF THE NHANES 2017 - 2020
Authors: Tantisattamo Ekamol , Wannaphut Chalothorn , Wattanachayakul Phuuwadith , Chaisrimaneepan Nattanicha , Lalitnithi Pakin , Lopimpisuth Chawin , Pangkanon Watsachon , Thimphitthaya Chanattha , Naunsilp Piengpitch 
Published: January 2023

Background:
Higher dietary calcium intake is associated with lower blood pressure. This association among different genders is unclear.

Methods:
A cross sectional study utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2018 included participants ≧18 years old. The Association between the quartile of the dietary calcium intake and systolic and diastolic hypertension defined as three average measured systolic blood pressure ≧130 and diastolic blood pressure ≧80 mmHg, respectively was examined by multiple logistic regression.

Results:
Of 11,137 study participants, the mean ± SD age was 50 ± 19 years old and 51% were female. Up to 35% were White followed by Black, Asian, and other races. Median (interquartile range; IQR) dietary calcium intake of quartile 1 to quartile 4 were 21 (13, 33), 120 (83, 183), 233 (220, 293), and 625 (500, 959) mg/day, respectively. Average systolic blood pressure and diastolic blood pressure were 124 ± 19 and 74 ± 12 mmHg, respectively. Systolic and diastolic blood pressure were significantly lower in women compared to men for every quartile 1 and 2 of dietary calcium intake, higher in quartile 3, and not different in quartile 4 (Figure 1A and 1B). Dietary calcium intake in quartiles 3 and 4 were significantly associated with 38% and 55% greater odds of systolic hypertension (odds ratio (OR) Q3 1.375, P 0.006, 95% confidence interval (CI) 1.095, 1.728 and OR Q4 1.550, P < 0.0001, 95%CI 1.249, 1.923), but not with diastolic hypertension. After adjusting for age, gender, race, body mass index, serum creatinine, urine albumin:creatinine ratio, dietary sodium and potassium intakes, and the interaction term between gender and dietary calcium intake, only dietary calcium intake in quartile 3 was significantly associated with 82% lower odds of systolic hypertension (adjusted OR Q3 0.164, P 0.005, 95%CI 0.047, 0.578), while the association was greater and in the same direction for quartile 4, but it was not statistically significant (adjusted OR Q4 0.341, P 0.120, 95%CI 0.087, 1.326). Although there was an inverse association between dietary calcium intake and diastolic hypertension, it was not statistically significant. Gender was identified as an effect modifier, with a stronger positive association between the dietary calcium intake and systolic hypertension observed in female participants (Pinteraction 0.028).

Conclusions:
Dietary calcium intake and systolic hypertension, but not diastolic hypertension is inversely associated with a different magnitude between women and men. Additional longitudinal studies are required to further evaluate this relationship.