bluuebunny/crossref_metadata_2025 huggingface dataset:
S-22-7: GENOMIC ANALYSES OF HYPERTENSION-ASSOCIATED DISEASES ACROSS ETHNIC GROUPS AND SPECIES
Authors: Kato Norihiro
Published: January 2023

To explore genetic architecture of hypertension and end-organ damages, we performed integrative genomic analyses in both humans and inbred hypertensive rat strains.

In humans, noting that hypertension is more prevalent and contributes to the increased risk of stroke in people of East Asian ancestry, we performed a multi-stage GWAS for blood pressure (BP) principally in East Asians and meta-analysis in East Asians and Europeans. We reported 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. Some of the ancestry-specific association signals are influenced by a selective sweep. These data provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.

In rats, we also performed genomic analyses of BP and related phenotypes in spontaneously hypertensive rats (SHR) and their substrain, stroke-prone SHR (SHRSP). By integrating whole-genome sequencing, transcriptome profiling, genome-wide linkage scans (maximum n = 1415) and fine congenic mapping (maximum n = 8704) plus comparative analysis with human, transcriptome-wide association study (TWAS) datasets, we searched causal genes and causal pathways for the tested traits. The overall results validated the polygenic architecture of elevated BP compared with a non-hypertensive control strain, Wistar Kyoto rats (WKY). We identified 26 potential target genes, including rat homologs of human TWAS loci, for the tested traits. In this analysis, we re-discovered 18 genes that had previously been determined to contribute to hypertension or cardiovascular phenotypes. Notably, five of these genes belong to the kallikrein-kinin/renin-angiotensin systems (KKS/RAS), in which the most prominent differential expression between hypertensive and non-hypertensive alleles could be detected in rat Klk1 paralogs.

Furthermore, to unravel the mechanisms underlying antihypertensive drug-induced amelioration of end-organ damages, we performed transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred rat strains (SHRSP and WKY). Noticeable changes of mRNA expression were induced particularly by RAS blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the KKS/RAS (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney.

Taken together, we provide genetic epidemiological evidence for ethnic differences in hypertension susceptibility and also in vivo experimental evidence supporting the presence of key disease pathways, such as KKS/RAS, likely across species.
S-23-2: CLINICAL SIGNIFICANCE OF WORK STRESS INDUCED INCREASE IN BLOOD PRESSURE IN HYPERTENSION MANAGEMENT
Authors: Munakata Masanori
Published: January 2023

We usually spend about one third time of a day for working. So it is critically important for our health if the working condition is comfortable or stressful. In many developed countries including Japan, retirement age tended to be delayed due to several reasons. This means that we must spend more time for work in our life. Elderly people are vulnerable to brain and heart diseases. So the establishment of less stressful work condition and risk management is increasingly important to prevent work-related cardiovascular events or Karoshi.

Among 203 Karoshi cases received worker compensation in Japan, 60 % died of stroke while remaining cardiovascular diseases. For occupational factor, long working has been considered as a risk of Karoshi. Meta-analysis has also shown that long working hours are associated with increased risk of cardiovascular diseases, especially for stroke. In Karoshi cases, most prevalent risk factor was hypertension (40%). However, the review of literature has shown that the relationship between long working hours and blood pressure increase or hypertension is inconsistent. Interestingly, some data showed that long working hours are associated with lower risk of hypertension, suggesting that the relationship between working long hours and blood pressure increase is confounded by other factors like qualitative work stress. Karoshi unexpectedly occur. Therefore in a real world, we need to obtain an individual information on blood pressure response during work to adequately manage work-related hypertension.

Ambulatory blood pressure monitoring is an ideal method to monitor blood pressure behavior during work but is not practical to perform repeatedly with short duration. Self-measurement of blood pressure may replace ambulatory monitoring to examine work-related blood pressure variation. We studied 207 treated hypertensive subjects working for 29 Rosai hospitals. Blood pressures and heart rate were measured by themselves with an automated device at standardized conditions 4 times a day: after waking, 10:00 h, 16:00 h, and before sleep on three days (Monday, Friday, and Saturday or Sunday). We could observe clear daily and weekly variation of rate pressure product (systolic blood pressure × heart rate). The increase in rate pressure product on Monday morning was significantly correlated with urinary albumin excretion and job strain index in women. Our data showed the feasibility of self-monitoring of blood pressure and heart rate at workplace. This method would be useful to monitor work-stress related hypertension in several overwork situation.
S-24-3: CURRENT TREND OF HYPERTENSION PRACTICE BY SPECIALISTS AND NON-SPECIALISTS IN THE JAPANESE PRIMARY CARE SETTINGS - J-DOME STUDY
Authors: Eguchi Narumi , Asayama Kei , Katsuya Tomohiro , Hatori Yutaka , Miyakawa Masaaki , Noda Mitsuhiko
Published: January 2023

Objective:

Measuring the quality of primary care practice in Japan is difficult due to insufficient clinical data. To change the situation, the first nationwide primary care registry trial in Japan called J-DOME was launched for type 2 diabetes mellitus in 2018, and expanded to assess hypertension by 2020. In this cross-sectional analysis, we compare the patients with hypertension managed by hypertension specialists with those by non-specialists in the primary care settings.

Design and Method:

A total of 2,161 patients with hypertension were registered in 2021 (1,583 by non-specialists and 578 by specialists). Data were registered to the web-based registry system directly by the participating doctors or their staff. Clinic office blood pressure (BP) captured at the last visit (mandatory item), and the most recent self-measured home BP (not mandatory) were registered. The registered data were analyzed and compared between the two groups classified by whether the physicians were hypertension specialists or not.

Results:

Average age, body mass index (BMI), and duration of hypertension were 69.7 years, 25.3 kg/m2, and 12.8 years in the non-specialist group and 70.5 years, 25.2 kg/m2, and 13.2 years in the specialist group, respectively. The average systolic/diastolic office BP was 134.9/75.2 mmHg in the non-specialist group and 134.9/75.7 mmHg in the specialist group, and patients with systolic BP > = 140 mmHg consisted of 34.2% and 35.8%, respectively. The average home BP was 127.9/75.7 mmHg in the non-specialist group (n = 722, 45.6% of this group registered home BP) and 125.9/74.9 mmHg in the specialist group (n = 419, 72.5%). The HbA1c in the hypertension non-specialist group averaged 6.6% compared with 6.2% in the specialist group (p < 0.001). The ratio of prescribed antihypertensive medications was significantly different between the non-specialist and specialist groups (Figure). As for education on sodium intake, 80.7% of the patients with non-specialists received the education compared to 91.8% of those with specialists, and the average daily sodium consumption was 9.0 g (n = 426) and 8.7 g (n = 365), respectively.

Conclusions:

Although the office BP and essential characteristics were similar, the evident differences between the specialist and non-specialist groups were identified in hypertensive medications and education on sodium intake. Furthermore, the number of home BP data registered in the non-specialist group was limited, which urges further promotion of home BP measurement. The J-DOME study will continue to call for far more registration to provide the benchmark of practice quality in Japanese primary care settings.
S-28-5: CIRCULATING ANGIOTENSIN CONVERTING ENZYME 2 ACTIVITY AS A CARDIOVASCULAR RISK MARKER IN A YOUNG HEALTHY POPULATION: THE AFRICAN-PREDICT STUDY
Authors: Gafane-Matemane Lebo F , Burrell Louise M , Patel Sheila K , Kruger Ruan , Schutte Aletta E
Published: January 2023

Objective:

Cardiovascular disease (CVD) remains the major contributor to premature death globally, with black populations presenting with a disproportionate burden of CVD and early target organ damage. Renin angiotensin system dysregulation is a key factor involved in hypertension development and organ damage in black populations. Angiotensin converting enzyme 2 (ACE2) counteracts the deleterious effects of angiotensin II, and increased circulating ACE2 predicts cardiovascular events and mortality in the general population, and in patients with CVD. However, the role of ACE2 activity as a cardiovascular risk marker in young healthy individuals remains largely unclear. We explored ethnic and sex differences in ACE2 activity and associations between blood pressure (BP), left ventricular mass index (LVMi) and ACE2 activity in young healthy black and white adults.

Design and method:

We included 1134 black (men, N = 280; women, N = 285) and white (men, N = 277; women, N = 292) participants aged 20–30 years. The participants were normotensive at screening (BP≦140/90 mmHg) with no known CVD. Ambulatory systolic and diastolic BP were recorded and LVMi (m2.7) was obtained from echocardiography and plasma ACE2 activity measured using a validated assay.

Results:

Overall, mean plasma ACE2 activity was higher in black [1.33 pmol/min/ml (0.02; 19.6)] than in white [0.73 pmol/min/ml (0.02; 12.5)] participants, and higher in men [3.63 pmol/min/ml (0.02; 20.5)] than in women [0.28 pmol/min/ml (0.02; 9.87)] (both P < 0.001). When comparing ethnic groups according to sex, ACE2 activity was higher in black men and women than in white men and women (both P ≦ 0.012). After adjustments for covariates (ethnicity, sex, age, body mass index, socioeconomic status, physical activity, glucose, low density lipoprotein cholesterol, C-reactive protein, alcohol intake and smoking), 24-hour systolic BP was positively associated with ACE2 activity in the total group (R2 = 0.43; β=0.07; P = 0.019) and black men (R2 = 0.19; β=0.18; P = 0.007). There were no independent associations of diastolic BP and LVMi with ACE2 activity in any of the groups.

Conclusions:

24-hour systolic BP was independently and positively associated with ACE2 activity in the total group. When stratifying the group according to ethnicity and sex, a similar association was evident in black men, a group previously identified to be at high cardiovascular risk. The observed ethnic and sex differences in ACE2 activity and associations with BP suggest that ACE2 may be a useful biomarker in cardiovascular risk profiling in young populations.
S-28-8: THE ASCOT LEGACY COHORT: THE LONG-TERM EFFECTS OF BLOOD PRESSURE AND BLOOD PRESSURE VARIABILITY ON CARDIOVASCULAR AND RENAL OUTCOMES
Authors: Sever Peter , Gupta Ajay , Whiteley William , Godec Thomas , Rostamian Somayeh , Mackay Judith , Poulter Neil , Whitehouse Andrew
Published: January 2023

Introduction:

We have previously shown that visit to visit systolic blood pressure variability (BPV) was the major predictor of cardiovascular outcomes in ASCOT, a trial in hypertensive participants randomised to amlodipine based or atenolol based treatment. Treatment differences in BPV accounted for the benefits of the amlodipine based regimen over the atenolol based regimen on cardiovascular (CV) events during the trial. We now report observations from the 20 yr follow up of UK participants to determine the long term impact of mean systolic blood pressure control during the trial and BPV on CV and renal outcomes.

Methods:

In the ASCOT Legacy Cohort, 7,092 hypertensive participants with hypertension, aged 40 to 79 years, with at least three other CV risk factors have been followed for up to 20 years. All available SBP visit records (n = 100,933) were included after excluding the first six months observations. The mean of SBP as a measure of BP control and the standard deviation (SD) of all SBPs as an estimate of visit to visit BPV were calculated for the five years of the trial. Participants were then followed for up to 15 years after the end of the trial using the UK National Health Service (NHS) electronic health records. CV and renal outcomes were measured using Cox proportional hazards model adjusted for confounding variables.

Results:

Although in trial mean SBP predicted long term CV and renal outcomes, SBP variability independent of mean SBP was a strong predictor of both CV and renal outcomes. (Table)

Those originally assigned amlodipine based (vs. atenolol based) treatment had a significantly reduced long term risk of risk of stroke [0.82, 0.72 to 0.93, p = 0.003], total CV events and procedures [0.93, 0.88 to 0.98, p = 0.008], total coronary events [0.92, 0.86 to 0.99, p = 0.024] and atrial fibrillation [0.91, 95% CI, 0.83 to 0.99, p = 0.030]. There was no significant difference in the incidence of heart failure, non fatal myocardial infarction and fatal CHD or renal events.

Conclusions:

Amlodipine based treatment conferred long term advantages over atenolol based treatment on several CV outcomes. Both mean SBP and BPV are strong predictors of long term CV and renal outcomes, but BPV, independent of mean BP, confers a significant additional risk and should be considered for future preventive and therapeutic strategies.
S-29-1: HYPERTENSION AND HEART FAILURE: NEW INSIGHTS
Authors: Komuro Issei
Published: January 2023

Heart failure has become a major problem all over the world because of a rapid increase in the number of patients and deaths. Although many drugs and devices have been developed, the prognosis of patients with heart failure is still poor. Hypertension, one of the largest risk factors of heart failure, induces cardiac hypertrophy by pressure overload (PO), leading to diastolic dysfunction early and finally to systolic dysfunction. Heart failure is also resulted from a variety of cardiac diseases such as myocardial infarction, valvular disease and congenital heart disease. Cardiac hypertrophy is often observed in these cardiac diseases, too, suggesting that cardiac hypertrophy is important as a preliminary step of heart failure. Single cell analysis of murine hearts revealed that PO changed transcripts so different from normal state first and then transcripts returned to near normal but they were not homogenous. There were two pathways from hypertrophied cardiomyocytes (CMs) after PO, failing and adaptive pathways. To elucidate how failing CMs are induced, we determined transcripts of the fork and found that there was a network of genes consisting of many targets of p53. CM specific p53 KO mice did not show HF after PO. Failing CMs were recognized in wild type mice but not in p53KO mice. Transcription pattern is conserved in human HF. There were two trajectories also in human, adaptive and failing. DNA damage response genes were expressed in failing CMs. The levels of DNA damage response genes were high in failing heart and were even higher in non-responder to treatments than responder. Transcripts of normal CMs are homogeneous and those of failing CMs are inhomogeneous. Many inflammatory cytokines were upregulated in failing CMs. IGFBP7, which is known to be secreted from DNA damage-induced senenscent cells, was upregulated in failing CMs. Random forest analysis revealed that there were many proteins in serum which are corelated to the progression of HF and IGFBP7 was the protein most corelated to that. IGFBP7 is mildly upregulated in non-advanced HF patients and robustly upregulated in advanced HT patients. These results suggest that PO induces DNA damage of CMs, leading to upregulation of inflammatory cytokines from senenscent CMs, finally resulting in the development of heart failure.
S-29-2: MEDICAL THERAPY FOR HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Kjeldsen Sverre Erik
Published: January 2023

Hypertension constitutes the major risk factor for heart failure (HF) with preserved ejection fraction (HFpEF); prevalences above 90% have been reported. HFpEF is a prevalent clinical syndrome with increased cardiovascular morbidity and mortality comparable to HFrEF. Long specific guideline-directed medical therapy (GDMT) for HFpEF was hard to establish due to lack of convincing positive outcome data from randomized controlled trials (RCTs) mainly because of major limitations of the available studies. Available evidence has however increased with recent and larger RCTs with statistical power. Besides, control of blood pressure (BP) is widely regarded as central to the prevention and clinical care in HFpEF. Thus, in current guidelines including the 2018 European Society of Cardiology (ESC) and European Society of Hypertension (ESH) Guidelines, blockade of the renin-angiotensin system (RAS) with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) provides the backbone of BP lowering therapy in hypertensive patients. Although superiority of RAS blockers has not been clearly shown in dedicated RCTs designed for HFpEF, except for in re-analysis with adjustment for commonly available baseline characteristics or repeat event analysis, we propose that this core drug treatment strategy is applicable for hypertensive patients with HFpEF with the addition of some modifications. The latter apply to the use of spironolactone (MRA) apart from the treatment of resistant hypertension and the use of the angiotensin receptor neprilysin inhibitor (ARNi). In addition, novel agents such as sodium-glucose co-transporter-2 inhibitors (SGLT2-i) and finerenone (non-steroidal MRA) represent promising therapies. Besides, beta-blocker therapy is widely indicated in 60–80% of HFpEF patients due to HT with rapid heart rate (>80 beats/min), rapid atrial fibrillation and/or coronary heart disease. The development of an effective and practical classification of HFpEF phenotypes and GDMT through dedicated high quality RCTs are coming towards firmer conclusions.
S-29-3: THE RELATIONSHIP BETWEEN VENTRICULAR-ARTERIAL COUPLING AND AEROBIC CAPACITY ACROSS THE CARDIOVASCULAR DISEASE CONTINUUM: FOCUS ON PROXIMAL AORTIC STIFFNESS
Authors: Pugliese Nicola Riccardo , Faita FRANCEsco , Ruschitzka Frank , Taddei Stefano , Williams Bryan , Canterin Francesco Antonini , Masi Stefano
Published: January 2023

Objective:

Ventricular-arterial coupling (VAC) can be evaluated as the ratio between arterial stiffness (pulse wave velocity, PWV) and myocardial deformation (global longitudinal strain, GLS). We evaluated VAC across the cardiovascular disease continuum.

Design and method:

We introduced a Doppler-derived, single-beat technique to estimate aortic arch PWV (aa-PWV) in addition to tonometry-derived carotid-femoral PWV (cf-PWV). We measured PWVs and 3D-GLS in:

We evaluated peak oxygen consumption (VO2) and peripheral extraction (AVO2diff) using combined cardiopulmonary-echocardiography exercise stress.

Results:

aa-PWV was obtainable in all subjects and significantly lower than cf-PWV in all subgroups (p < 0.01). PWVs were directly related and increased with age (all p < 0.0001). cf-PWV/3D-GLS was similarly compromised in HFrEF (1.08 ± 0.36) and HFpEF (1.05 ± 0.22), while aa-PWV/3D-GLS was more impaired in HFpEF (0.69 ± 0.11) than HFrEF (0.60 ± 0.15; p < 0.01). Stage A-B had values of cf-PWV/3D-GLS and aa-PWV/3D-GLS (0.66 ± 0.25 and 0.47 ± 0.12) higher than controls (0.47 ± 0.10 and 0.40 ± 0.10) but lower than Stage C (all p < 0.01). Peak AVO2diff was inversely related with cf-PWV/3D-GLS and aa-PWV/3D-GLS (all p < 0.01). cf-PWV/3D-GLS and aa-PWV/3D-GLS independently predicted peak VO2 in the overall population (adjusted R2 = 0.32 and 0.35; all p < 0.0001) but only aa-PWV/3D-GLS was independently associated with flow reserve during exercise (R2 = 0.51; p < 0.0001).

Conclusion:

Abnormal VAC is directly correlated with greater severity of HF and worse functional capacity. HFpEF shows a worse VAC than HFrEF when expressed by aa-PWV/3D-GLS.
S-30-1: THE IMPORTANCE OF MULTIDISCIPLINARY INTERVENTION FOR THE PREVENTION OF CVD IN JAPAN
Authors: Kabayama Mai , Kamide Kei
Published: January 2023

Preventing illness and promoting health is important for prolonging healthy life expectancy, and it also leads to the reduction of medical and long-term care costs. As Japan has entered a super-aged society, prevention of CVD, which causes stroke and dementia, the main causative diseases of the need for long-term care, is becoming more important. In addition, it is necessary to widely implement these CVD prevention strategy from an early stage. In other words, not only the tertiary preventive measures after the onset, but also the secondary preventive measures that extract high-risk populations and the primary preventive measures that approach the entire community are required.

Under these circumstances, the specific health checkup and specific health guidance system was started in 2008 in Japan. This system has a new concept in which medical insurers take the lead in implementing it, and aims to prevent the onset of illness by providing lifestyle modification support to people at high risk of metabolic syndrome. This system has been established nationwide and has been successful. On the other hand, there are not a few people who leave medical treatment of lifestyle-related diseases, discontinued treatment, or even have not received medical checkup, which is an urgent issue. It is expected that various medical professionals will provide health guidance for those undergoing treatment, encourage continuous treatment, support for improving adherence, along with the nationwide health promotion such as increasing the rate of people taking health checkup or improvement of healthy environment in the community and workplace.

The extension of healthy life expectancy for the entire nation will be realized by strengthening of cooperation between preventive intervention and medical care by various medical professionals. In the session, we will outline the current status of multidisciplinary collaboration efforts of health professionals in community, and introduce the examples of RCT results of nurse-led alcohol guidance effects in hypertensive outpatient clinics that we have conducted.
S-30-6: PROMOTION OF DIVERSITY AND INCLUSION (D&I) BY THE JAPANESE SOCIETY OF HYPERTENSION (JSH): JSH ASAHIKAWA DECLARATION
Authors: Nakamura Satoko
Published: January 2023

The JSH D&I Committee has been developing various activities related to D&I since 2012. In 2018, we published JSH Statement: Asahikawa Declaration in Promotion of Diversity by the Japanese Society of Hypertension - the JSH Asahikawa Declaration in Hypertension Research. We would like to summarize the activities so far and make use of them in future activities.

First, we conducted a questionnaire on the web, grasped the current situation, and set numerical targets. Since then, we have promoted various activities in response to the needs of our members. (1) JSH Women Investigators Award presentation since 2015, (2) Setting up a committee booth at annual meetings to disseminate information, (3) As part of nurturing the next generation, cooperation with the nursery room, start of academic conference tours for children, and cooperation in plans for low-salt education, (4) Promoting website creation and publicity activities, (5) Holding unique lectures at annual meetings, (6) Discovering female human resources, and (7) Appointing medical professionals other than doctors to the committee.

Compared to 2014, the number of female members, medical specialists, councilors, chairpersons, speakers, committee chairs, etc. has increased.

In this way, D&I activities at JSH have started and are developing. As an activity for ISH2022, we will introduce the contents of a recent member awareness survey. We will continue to listen to the opinions and requests of our members, and we would like to develop it as a meaningful committee through concrete measures and initiatives.
S-31-4: STROKE BURDEN AND HYPERTENSION IN THE ASIA-PACIFIC REGION
Authors: Venketasubramanian Narayanaswamy , Chadachan Veerendra , Sule Ashish Anil , Tay Jam Chin , Chee Tek Siong , Wong Emmett Tsz Yeung , Koh Tian Hai , Low Lip Ping , Oh Vernon Min Sen , Wu Akira , Handa Pankaj , Teo Jimmy Boon Wee
Published: January 2023

Background:

Stroke is a major cause of death and disability globally, especially in particular in the Asia-Pacific region, which is home to more than 4 billion people. Among the modifiable risk factors for stroke, hypertension is the strongest, but controllable to confer large outcome benefits.

Objective:

To investigate the association between hypertension and stroke burden in Asia-Pacific countries.

Design and Methods:

Stroke burden, as defined as age- and sex-standardised disability-adjusted life-years lost (DALYs) per 100,000 persons attributed to stroke, in Asia Pacific countries was extracted from the Global Burden of Disease (GBD) Study 2010. The age- and sex-standardised prevalence (%) of hypertension, defined as systolic blood pressure > 140 mmHg and diastolic blood pressure > 90 mmHg among adults aged 18 years or older, in these same countries was obtained from the World Health Organisation (WHO) database for 2015. Linear correlation was then estimated by calculating Pearson's product-moment correlation coefficient.

Results:

The stroke burdens expressed in terms of DALYs were obtained for 26 countries in the Asia Pacific region. The number of DALYs varied widely. being the lowest in Australia (398.2/100,000) and New Zealand (440/100,000), and the highest in Mongolia (4,409.8/100,000) and Indonesia (3,382.2/100,000). The prevalence of hypertension, also highly variable, was lowest in South Korea (11.0%) and Singapore (14.6%), and highest in Pakistan (30.5%) and Nepal (29.6%). There was a modest positive correlation between DALYs attributed to stroke and hypertension prevalence (r = 0.49). Approximately one-quarter of the variance in the DALYs due to stroke was predictable from the variability in hypertension prevalence across the Asia-Pacific region (r2 = 0.24).

Conclusion:

Both the burden of stroke and hypertension prevalence vary widely among Asian Pacific countries. There is a modest positive correlation between the two parameters. A significant amount of the variability in stroke burden is attributable to the variability in hypertension prevalence.
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-38-1: EPIGENETIC MECHANISM OF SALT-SENSITIVE HYPERTENSION
Authors: Fujita Toshiro
Published: January 2023

Nutritional and environmental factors contribute to the development of salt sensitive hypertension. DNA methylation, the most extensively studied epigenetic marker, may have more stable, longer lasting effects than transient changes in gene expression. Protein malnutrition during pregnancy causes prenatal programmed salt sensitive hypertension via aberrant DNA methylation of the angiotensin receptor, which is induced by exposure to excessive glucocorticoid in the fetal hypothalamus. In adults, salt sensitive hypertension induced by obesity is attributable to increased renal activity of Rac1 and mineralocorticoid receptor (MR) pathway, and adverse prenatal exposure induces transgenerational hypertension through activation of Rac1 and MR pathway by an epigenetic regulated mechanism. Finally, DNA methylation of Klotho in aged kidneys leads to a reduction in the circulating levels of soluble Klotho, and in turn, resulting in the activation of noncanonical Wnt5a and RhoA signaling in the vasculature and the development of aging associated salt sensitive hypertension. These findings indicate that epigenetic modulation has an important role in the development of salt sensitive hypertension throughout life.
S-38-2: PREVENTION OF EXPERIMENTAL GENETIC HYPERTENSION - GENOMIC CLUES FROM THE KIDNEY
Authors: Byars Sean , Prestes Priscilla , Suphapimol Vara , Vries Nathan De , Melo Mariana Del Rosso Le , Maier Michelle , Samani Nilesh , Berka Jennifer Wilkinson , Allen Andrew , Charchar Fadi , Harrap Stephen
Published: January 2023

Brief treatment with renin-angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this reprogramming, but relevant molecular genetic changes are unknown. We studied SHR kidney RNA differential expression (controlling for non-specific effects of lower BP) and DNA methylation 6 weeks after treatment with the angiotensin receptor blocker losartan from 10 to 14 weeks of age. RNA sequencing revealed a significant 6-fold (P < 0.0001) increase in renin gene (Ren) expression during treatment. Six weeks later direct mean arterial pressure remained lower than untreated SHR (123 vs 140 mmHg, P = 0.001) and kidney Ren expression was reduced by 23% (P = 0.03) and DNA methylation within the Ren promoter region was significantly increased (P = 0.04). Experiments with the ACE inhibitor perindopril and renin immunohistochemical analyses confirmed significant long-term reduction in kidney Ren expression following RAS inhibition. Genomic RNA sequencing analysis identified 13 candidate genes (Grhl1, Ammecr1l, Hs6st1, Nfil3, Fam221a, Lmo4, Adamts1, Cish, Hif3a, Bcl6, Rad54l2, Adap1, Dok4) and the miRNA miR-145-3p that were significantly differentially expressed and correlated closely with decreased Ren expression. Ten of the candidates were central to gene networks that exhibited significant enrichment for genes relevant to BP and the RAS. We propose that reduced renin gene expression is a legacy of early RAS inhibition and responsible for the persistent reduction in BP in SHR.
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.