bluuebunny/crossref_metadata_2025 huggingface dataset:
PS-BPP04-1: CLINICAL CHARACTERISTICS OF UNAWARE-UNTREATED HYPERTENSIVE SUBJECTS: FINDINGS FROM A JAPANESE HEALTH CHECKUP
Authors: Fujishima Shinichiro , Kodama Satoko , Sakai Togo , Abe Isao , Tsuchihashi Takuya
Published: January 2023

Background and Objective:

Hypertension (HT) is one of the most important risk factors for cardiovascular disease; however, about 30% of hypertensive subjects in Japan are estimated to be left unaware-untreated. The authors studied clinical characteristics of unaware-untreated HT (UAUT-HT) subjects using data of a large health checkup and public medical insurance.

Methods:

In a Japanese city, 54,287 persons underwent a public health checkup for 40–74 years old in 2017. The information on their medical diagnosis were obtained from the national medical insurance system. Among all examinees, 28,167 (51.9%) were hypertensive (systolic blood pressure (SBP) > = 140 mmHg, diastolic BP (DBP) > = 90 mmHg, took antihypertensive agents, or had diagnosis of hypertension on the national medical insurance system). If subjects took antihypertensive agents or had HT diagnosis, they were considered as aware HT. If not, the subjects were considered as UAUT-HT. Demographic factors were compared between UAUT-HT and aware HT.

Results:

Of all HT subjects, 13,426 (47.7%) were SBP < 140 and DBP < 90 mmHg (well controlled) under treatment, 6,727 (23.9%) were BP > = 140 /90 mmHg (poorly controlled) under treatment, 3,147 (11.2%) were aware of HT but untreated, and 4,867 (17.3%) were UAUT-HT. Compared with aware HT, the UAUT-HT group was younger (age < 65y; UAUT-HT, 25%; aware HT, 16%), leaner (BMI> = 25; 27%, 36%), had more female (57%, 52%), more subjects without proteinuria (82%, 75%), higher SBP and DBP (SBP, 148 ± 11, 136 ± 16; DBP, 85 ± 10, 78 ± 11), lower fasting blood glucose (99 ± 34, 103 ± 23, mg/dl), lower HbA1c (5.8 ± 0.7, 5.9 ± 0.8, %), higher LDL-cholesterol (133 ± 33, 120 ± 30, mg/dl), lower serum uric acid (5.2 ± 1.3, 5.4 ± 1.3, mg/dl), and higher eGFR (71 ± 13, 67 ± 14, ml/min/1.73^2). These were all significant differences (p < 0.01).

Conclusion:

These results suggest that the UAUT-HT subjects are young and have favorable health condition except for high BP and LDL-cholesterol level compared with aware HT. In such relatively healthy subjects, blood pressure may not be paid enough attention to consult and treat. Social enlightenment on HT for broader population may be needed.
PS-BPP05-3: ESTIMATED IMPACT OF MEDICATION DISPENSING REFORMS FOR PUBLIC HYPERTENSION TREATMENT COVERAGE IN INDIA
Authors: Marklund Matti , Mattingly T Joseph , Sahoo Swagata Kumar , Moran Andrew E , Appel Lawrence J , Matsushita Kunihiro
Published: January 2023

Background:

Reforms to scale up hypertension treatment are needed in India, where < 20% of individuals with hypertension have controlled blood pressure. Limited medication supply and short prescription periods are two key barriers to increase hypertension treatment coverage in the public health system.

Objective and Design:

We estimated the benefits on medication coverage of three medication dispensing reforms to increase hypertension medication coverage in India's public health system. The reforms included: 1) Increased use of single pill combinations (SPC, i.e., multiple medication classes within a pill); 2) Focused procurement by reducing the number of antihypertensive medication classes (from n = 5 to n = 3) and selecting one medication within class (e.g., amlodipine for calcium channel blockers) to be procured; and 3) Extended prescription duration (from one to three months) to reduce medication refill frequency. The alternative scenarios assuming implementation of individual or combined reforms were compared to a base case scenario (no use of SPC, current procurement of multiple medications across classes, and 1-month prescription duration). For each scenario, the maximal number of patients that could receive adequate medication was estimated using constrained optimization with a fixed budget (i.e., the cost of procuring and dispensing medication for n = 1,000 patients in the base case scenario). Microsimulation was utilized to simulate medication dispensation for individual patients, each with a specific medication requirement. Key input data on prescription patterns and medication costs were derived from publicly available sources.

Results:

We estimated that, at the same total costs as the base case scenario, ∼25% more patients could receive sufficient medication if either the use of SPC increased or if the number of medication types procured and dispensed was restricted (Figure). Even greater medication coverage was estimated if both reforms were combined (+63%,) or if all patients were dispensed SPC (+80%). Extending the prescription duration from one to three months was estimated to alone increase the medication coverage by ∼40% and could substantially enhance the effects of the other reforms when combined (e.g., Figure). The combination of only SPC and 3-month prescription can almost triple the number of patients able to receive antihypertensive medication.

Conclusion:

In India's public health care system, without additional costs to the health system, three reforms (increasing SPC use, restricting the number of medication types, and extending prescription periods) could substantially increase the number of patients to receive hypertension medications. Our study encourages the combination of these reforms to improve hypertension management coverage in India.
PS-BPP05-4: PRESCRIPTIONS OF ANTIHYPERTENSIVE DRUGS ARE INFLUENCED BY THE CHARACTERISTICS OF GENERAL PRACTITIONERS AND THEIR PATIENTS
Authors: Humbert Xavier
Published: January 2023

Background:

Hypertension is associated with significant cardiovascular morbimortality. However, hypertension control is low, especially in France. The reasons influencing general practitioners (GP) prescription of antihypertensive drugs (AD) remains unclear. This study aimed at assessing the influence of GP and patient characteristics on AD prescriptions.

Methods:

A cross-sectional study based on a sample of 2,165 GPs working with French national health insurance was realized in Normandy (region of France) in 2019. Only GPs meeting the criteria for full-time GP practice were included. The ration of AD prescription to overall prescription volume, a relative measure of AD prescription level, was calculated for each GP and permited the low-high AD prescriber definition. Associations of this AD prescription ratio with GP age, gender, practice location, number of years of practice, number of home visits and consultations, number and age of registered patients, patient income and number of patient with a chronic condition were assessed using univariate and multivariate analysis.

Results:

The low prescribers GPs were 51.3 ± 11.2 year-old and were mainly women (56%) and practiced in urban context (53%). They prescribed less antihypertensives drugs (4% vs 8%, p < 0.001) and had more low-income patients (6% vs 4%, p < 0.001). In the multivariate analysis, low prescribers were associated to urban practice (OR: 1.47, 95%CI: 1.14;1.88), GP younger age (OR: 1.87, 95%CI:1.42;2.44), patients younger age (OR: 3.39, 95%CI: 2.77;4.15), more patients consultations (OR: 1.33,95%CI: 1.11;1.61), more low-income patients (OR: 1.44, 95%CI: 1.17;1.76) and less diabetes mellitus patients (OR: 0.72, 95%CI:0.59;0.88).

Conclusions:

Our study described a profile of the typical low er AD prescriber GP. In future work, a more detailed assessment of all components of the consultation (in particular home blood pressure monitoring use) is necessary to explain AD prescription in general practice.
PS-BPP06-3: NON-HIGH-DENSITY LIPOPROTEIN CHOLESTEROL LEVELS AS A RISK FACTOR FOR SHORT-TERM MORTALITY IN ELDERLY CHINESE: A POPULATION-BASED COHORT STUDY
Authors: Li Yan , Yuan Hong , Lu Yao
Published: January 2023

Background:

Non-high density lipoprotein (non-HDL) levels were an important predictor of cardiovascular disease risk. However, it is unclear the relationship between non-HDL and mortality risk. This study explores the relationship between non-high-density lipoprotein levels and the risk of mortality, and the impact on long-term and short-term mortality risk.

Methods:

We analysis 621,164 elderly individuals from healthcare management receiving check-up in China basic public health service in 2010–2020. We analyzed the non-linear rela-tionship between non-HDL and all-cause and cause-specific mortality in patients receiving lipid-lowering treatment or not. Finally, the relationship between non-HDL and long-term or short-term mortality was investigated.

Results:

26,758 (4.3%) deaths were recorded at a mean follow-up of 2.03 years. The association between non-HDL and mortality was non-linear for elderly individuals. After multivariable adjustment, individuals with non-HDL < 3.29 mmol/L and > = 4.85 mmol/L increase the risk of all-cause mortality and cardiovascular mortality compared to non-HDL of 3.29 - 4.85 mmol/L. Only non-HDL < 3.29 mmol/L significantly increase the risk of cancer mortality (HR: 1.11; 95% CI: 1. 04 - 1.18, P < 0.001) and other mortality (HR: 1.16; 95% CI: 1.10 - 1.22, P < 0.001). Non-optimal concentrations of non-HDL had significant effects on both the long-term and the short-term risk of mortality, but the effect was more powerful for short-term (3 months) mortality. The non-optimal concentrations of non-HDL significantly in-creased the risk of all-cause mortality, cardiovascular mortality, and cancer mortality within 3 months. The association between non-HDL and all-cause and cause-specific mortality was not statistically significant in the elderly population receiving lipid-lowering treatment.

Conclusions:

Non-HDL was non-linearly associated with the risk of mortality, and non-optimal con-centrations of non-HDL significantly increased short-term mortality in elderly Chinese. As the possibility of confounding may exist, further research is necessary.
PS-BPP06-4: AGE-DEPENDENT INCREASE IN DIETARY SALT INTAKE IN THE JAPANESE ADULTS
Authors: Dohi Yasuaki , Sugiura Tomonori , Takase Hiroyuki
Published: January 2023

Objective:

More than half of all cardiovascular disease deaths have been attributed to high blood pressure. Although numerous factors are involved in the development of hypertension, excess dietary salt intake is quite important because it is a modifiable factor. Obviously, tracking alterations in salt intake with age is important for developing population-based strategies to lower salt intake. However, how salt intake changes with age at the individual level has not been intensively studied in the general population. Thus, the present study was designed to investigate changes in salt intake with age in individuals in the general population.

Design and Methods:

In this observational follow-up study, apparently healthy men and women age > 30 years who participated in a baseline medical checkup (2008–2009) at our center and had a medical checkup 10 years later (n = 2598) were enrolled. Salt intake was estimated by spot urine analysis. Yearly changes in salt intake were also assessed in participants with complete annual data over the course of 10 years from baseline (n = 1543).

Results:

The follow-up study demonstrated increased salt intake (8.8 ± 2.0 to 9.3 ± 2.1 g/day, P < 0.001) with increasing age (54.0 ± 9.7 to 64.0 ± 9.8 years). Salt intake increased year over year in participants who had a health checkup annually for the 10-year follow-up period (n = 1543; analysis of variance, P < 0.001). The increase in salt intake with age correlated with an increase in blood pressure. Then, regional levels of salt intake in the baseline period (between July 2008 and June 2009) and the period 10 years later (between July 2018 and June 2019) were compared using cross-sectional analyses. The propensity-matched model revealed similar regional levels of salt intake in the baseline period (8.9 ± 2.0 g/day, 55.8 ± 11.1 years, n = 5018) and at 10 years (8.8 ± 2.0 g/day, P = 0.21; 55.9 ± 13.0 years, P = 0.65, n = 5105).

Conclusions:

Dietary salt intake gradually increased with age in men and women in the general population during the 10-year follow-up period. This should be considered in devising for population-based strategies to lower dietary salt intake.
PS-BPR01-3: DISSOCIATION OF SERUM ALDOSTERONE CONCENTRATIONS BETWEEN THE MEASUREMENT METHODS: A CASE REPORT
Authors: Torimitsu Takuto , Kinouchi Kenichiro , Kato Kyosuke , Iwahara Akihide , Kozuma Takahide , Nakamura Toshifumi , Kobayashi Sakiko , Miyashita Kazuki , Itoh Hiroshi
Published: January 2023

A 89-year-old woman was admitted to our hospital for syncope in 20XX-13. During the hospitalization, hypertension was pointed out. Despite 4 cm left adrenal mass suggestive of myelolipoma in contrast-enhanced magnetic resonance imaging (MRI), the serum and urine hormone levels in relation to secondary hypertension was within normal limits. Diagnosis of essential hypertension was made and treatment with olmesartan and azelnidipine was begun. In 20XX-5, her blood pressure was well controlled, and serum aldosterone level and active renin concentration (ARC) were 167 pg/ml and 6.8 pg/ml, respectively. Annual computed tomography (CT) scans showed virtually the same size of the adrenal tumor over 5 years. The trend toward increase in her blood pressure prompted us to repeat a blood test in 20XX, which turned out that serum aldosterone concentration was extremely high (1144 pg/ml), while ARC was suppressed to 1.7 pg/ml. In light of positive captopril challenge test, primary aldosteronism was suspected, and she was admitted to our hospital. However, systolic blood pressure was only mildly elevated (130 mmHg), though blood pressure medication had not been changed for 5 years. In addition, serum potassium value was 4.7 mEq/L and 24-hr urinary aldosterone was merely 3.4 μg/day under the salt-loaded state, which was inconsistent with exceedingly high serum aldosterone concentration and argued against the diagnosis of primary aldosteronism. Hence, validity of the method to quantitate serum aldosterone levels was questioned. To determine serum aldosterone concentration, radioimmunoassay (RIA) was applied in 20XX-5, yet chemiluminescent enzyme immunoassay (CLEIA) has been introduced since 20XX. Strikingly, reexamination of the same serum sample discovered that serum aldosterone value of 770 pg/ml in CLEIA was equivalent to 59 pg/ml by RIA method. As such, marked dissociation seems present between the two types of assays in this particular patient. Although tendency of correlation with regard to serum aldosterone levels between the two methods have been clarified, attention needs to be paid for the exception as in this case. Thus, it is fundamental to thoroughly evaluate patients with suspected primary aldosteronism as to whether the clinical course and serum aldosterone levels are compatible, and if not, it may be necessary to change the measurement method.
PS-BPR01-4: A CASE OF ALDOSTERONE-PRODUCING ADENOMA DIAGNOSED BY ADRENAL ARTERIOGRAPHY AND BRANCH SELECTIVE ADRENAL VENOUS SAMPLING
Authors: Nishikawa Masaru , Kinouchi Kenichiro , Kobayashi Sakiko , Miyashita Kazutoshi , Takeda Toshikazu , Tamura Masashi , Nakatsuka Seishi , Mizutani Yosuke , Otomo Yusuke , Aoyama Kazuki , Yokota Kenichi , Kurihara Isao , Itoh Hiroshi
Published: January 2023

Case report:

A 43-year-old man had been followed up for hypertension and hypokalemia, but self-interrupted his hospital visits for the last four years. Based on the serum potassium level of 2.7 mEq/L, plasma aldosterone concentration of 202 pg/mL, and plasma renin activity of 1.1 ng/mL/hr, he was suspected of primary aldosteronism and was admitted to the previous hospital. A saline suppression test and a rapid ACTH stimulation test were both positive, and 24-hr urinary aldosterone level was 19 μg/day under sodium loading of 170 mEq/day, leading to the diagnosis of primary aldosteronism. Since contrast-enhanced CT showed an 8 mm-sized adenoma in the lower portion of the left adrenal gland, an aldosterone-producing adenoma was suspected and a non-segmental adrenal venous sampling (AVS) was performed. However, it yielded apparent bilateral aldosterone suppression in the main trunk of the bilateral adrenal veins, where the aldosterone-to-cortisol (A/C) ratio was lower than that in the inferior vena cava even after ACTH loading. The patient was referred to our hospital for a segmental AVS. Arteriography was first performed from the left inferior adrenal artery to confirm the outflow vessels from the adenoma. Strikingly, there was an aberrant vein which drained into the proximal segment of the left adrenal vein. CT imaging at the time of arteriography revealed, in addition to the known adenoma, a 6 mm-sized micronodule in the lateral region of the left adrenal gland, and the aberrant vein appeared to be the main outflow vessel from the micronodule. A segmental AVS was performed, and blood samples were taken from the bilateral adrenal veins including the aberrant vein and the main trunk of the left adrenal vein proximal to its confluence. The A/C ratio was highest in the aberrant vein, followed by in the main trunk of the proximal left adrenal vein, while it was markedly suppressed in other branches and the main trunk of the left adrenal vein distal to the confluence of the aberrant vein. Based on these results, the presence of aldosterone-producing adenoma in the left adrenal gland was suggested. Laparoscopic partial left adrenalectomy was performed without postoperative complications. Hypertension and hypokalemia were fully resolved afterwards.

Conclusions:

Adrenal arteriography and segmental AVS should be considered in such cases that apparent bilateral aldosterone suppression is noted in conventional AVS in patients with clinically suspected aldosterone-producing adenoma.
PS-BPR02-9: RECURRENCE OF RENAL ARTERY STENOSIS BY PONATINIB, A MULTI-TARGETED TYROSINE-KINASE INHIBITOR
Authors: Kusahana Ei , Wakino Shu , Kanda Takeshi , Itoh Hiroshi
Published: January 2023

Introduction:

Cardiovascular disease and drug induced hypertension have been reported with tyrosine-kinase inhibitor including ponatinib treatment in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). We report bilateral renal artery stenosis (RAS) in a patient who had received ponatinib for relapsing Ph+ALL after 2nd allogeneic stem cell transplantation.

Case:

A patient was a 40-year-old woman with no history of cardiovascular disease and hypertension. She developed myocardial damage that appeared to be ponatinib -induced, and catheterization of the heart revealed multiple coronary artery lesions and started optical medical therapy. 16 months after ponatinib treatment, she was referred to the nephrology department for evaluation of hypertension and increase in serum creatinine from 1.47 to 2.02 mg/dL. Renal ultrasonography and MRI revealed significant stenosis of the right renal artery, and angiography and stenting were performed. 5 months after the stent treatment, progression of renal dysfunction due to exacerbated RAS was observed. Intravascular ultrasonography revealed diffuse intimal thickening occurred in-stent restenosis, and balloon dilation was performed. She required balloon dilatation a total of three times even after the discontinuation of ponatinib treatment. The patient was thought to have systemic vascular endothelial damage caused by ponatinib.

Discussion:

It should be considered when hypertension and renal dysfunction occurs after ponatinib use
PS-BPR03-5: A CASE OF LIDDLE SYNDROME-LIKE REFRACTORY HYPERTENSION WITH TREATMENT-RESISTANT HYPOKALEMIA COMPLICATED BY NEPHROTIC SYNDROME DUE TO DIABETIC NEPHROPATHY
Authors: Mori Tatsuhiko
Published: January 2023

A 62-year-old woman had been treated for diabetic nephrotic syndrome, hypokalemia, and edema with perindopril, furosemide, potassium L-aspartate, valsartan, and spironolactone since January, X. On May 15, X, fatigue and nausea appeared, and on the morning of May 20, these symptoms increased. On the morning of May 20, she visited the hospital. She was urgently admitted to the hospital because of prominent edema in both lower limbs, elevated blood pressure (164/83 mmHg), marked hypokinemia (K 2.4 mEq/L), and metabolic alkalosis (pH 7.612, HCO3- 31.3 mmol/L) in the arterial blood gas. Post-hospitalization examination revealed hyporeninemia and hypoaldosteronemia. Since administration of spironolactone in addition to previous medications failed to improve the hypokaremia and hypertension, triamterene 100 mg was added. The treatment was resulted in rapid hypotension, accompanied by improvement of hypokalemia and metabolic alkalosis. The dose of triamterene was later reduced to 50 mg, and excess blood pressure lowering was improve. Genetic testing did not identify any mutations in the beta or gamma subunits of the ENaC gene. Discussion: In this patient, no hypokalemia was observed in previous examinations. The hypokalemia in this patient was spironolactone-resistant, and the fact that triamterene, a distal tubular epithelial Na channel (ENaC) inhibitor, was effective in this patient; furthermore, no genetic abnormality in ENaC, suggests the possibility of an acquired ENaC abnormality similar to the Liddle syndrome.
PS-B03-1: MECHANISM FOR INCREASED BLOOD PRESSURE VARIABILITY AND EFFECT OF AZELNIDIPINE IN RATS INFUSED WITH NORADRENALIN
Authors: Jiang Danfeng , Matsuzaki Minami , Kawagoe Yukiko , Kitamura Kazuo , Tsuruda Toshihiro , Kaikita Koichi , Asada Yujiro , Kato Johji
Published: January 2023

Objective:

Augmented blood pressure variability (BPV) has been shown to be associated with cardiovascular diseases. There are various types of BPV depending on time periods for which BP levels are evaluated, while there are reportedly factors, such as aging and stiffened large arteries, which are related to any type of BPV. However, the mechanistic relationships between these factors and augmented variability remain to be specified. Recently, we found that 24-h BPV was augmented following continuous infusion of noradrenalin (NA) over 14 days in rats, assuming this animal as a model of augmented BPV of 24-h ambulatory BP monitoring (ABPM) of humans. The aim of the present study was to explore the mechanism underlying NA-induced BPV and the pharmacological action of the calcium channel blocker (CCB) azelnidipine, focusing on alterations in baroreceptor reflex sensitivity (BRS) and morphological findings of the aortic arch, where baroreceptors are thought to be located.

Methods:

Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 ug/h NA with or without oral administration with 30 mg/kg/day azelnidipine for 14 days. BPV was evaluated by a coefficient of variation (CV) of BP recorded every 15 min under an unrestrained condition via an abdominal aortic catheter by a radiotelemetry system. To estimate BRS, data obtained from continuous BP monitoring were analyzed by a sequence technique with the software HemoLab. Sections of the aortic arch were stained with hematoxylin-eosin, and cross-sectional areas were determined by computerized measurement.

Results:

CVs of systolic and diastolic BP during 24-h period almost doubled at day 7 and 14 following continuous infusion of NA. Increased 24-h variabilities were accompanied by impaired BRS (P < 0.01) and thickened aortic media (P < 0.01) at day 14 of the infusion. Meanwhile, azelnidipine administration mostly (P < 0.01) suppressed NA-induced BPV, and significantly (P < 0.01) alleviated impairment of BRS and aortic medial thickening. When analyzed for all groups by a simple regression, CV of systolic BP at day 14 significantly correlated with reduction in BRS (r = 0.45, P < 0.01), which was associated with aortic medial area (r = 0.57, P < 0.01).

Conclusions:

The present findings suggest a possible mechanism underlying NA-induced BPV: aortic arch stiffened by medial thickening may be partly involved in impaired BRS, resulting in augmented BPV. Meanwhile, azelnidipine alleviated BPV, preserving BRS probably via inhibition of NA-induced aortic medial thickening in rats.
PS-B03-4: A NOVEL SOLUBLE EPOXIDE HYDROLASE VACCINE PROTECTS MURINE CARDIAC MUSCLE AGAINST MYOCARDIAL INFARCTION
Authors: Shikraki Aya , Kitsuka Takahiro , Oyama Junichi , Nakagami Hironori , node Koichi
Published: January 2023

Objective:

Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction.

Design and method:

We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeicosatrienoic acids (EETs), which have vasodilatory and anti-inflammatory properties. The several amino acid sequence of Soluble Epoxide Hydrolase (sEH) protein was designed as peptide vaccine. The 40 rats were injected the vaccine subcutaneously and the other 30 rats were injected the saline solution and adjuvant four times in every two weeks. The left anterior descending artery was ligated in both groups as myocardial infarction model, and those hearts were evaluated by cardiac echography and cardiac tissue were examined histologically on day7 after the surgery.

Results:

In the vaccine group, the ischemic area was significantly reduced, and systolic cardiac function was significantly preserved. Vaccine treatment clearly increased microvessels in the border area and suppressed fibrosis in the cardiac tissue secondary to myocardial infarction. Furthermore, VEGF and eNOS expression were upregulated in the cardiac tissue of the vaccine group, suggesting induced EETs caused neovascularization through modifying protein expression.

Conclusions:

We successfully made a new vaccine to inactivate soluble epoxide hydrolase, and we have evaluated the effect of the vaccine in a rat myocardial infarction model. The soluble epoxide hydrolase vaccine is a novel treatment for improving cardiac function following myocardial infarction.
PS-B03-10: EPLERENONE INHIBITS ICAM-1 FROM MACROPHAGES AND MACROPHAGE-TO-MYOFIBROBLAST TRANSITION IN TYPE 4 CARDIORENAL SYNDROME RATS INDUCED WITH UUO
Authors: Han Yutong , Xian Yunqian , Shimosawa Tatsuo , Chang Yi , Xu Qingyou
Published: January 2023

Objective:

The type 4 cardiorenal syndrome (CRS) represents the kidney-heart relationship in a pathological situation where cardiovascular complications dominate all causes of death in patients with chronic kidney disease (CKD), but the underlying mechanism of CKD-induced cardiac disease have not been fully clarified. We reported that aldosterone directly stimulates cardiac fibrosis, whereas macrophage-to-myofibroblast (MMT) is associated with fibrosis. However, the mechanistic basis of this pathogenic pathway that promotes cardiac fibrosis remains to be elucidated.

Design and method:

We used a 180-day rat model of unilateral ureteral obstruction (UUO) to replicate the CRS model and RAW264.7 cells in-vitro studies. Using eplerenone, a blocker of mineralocorticoid receptor (MR), to test the effect of aldosterone in cardiac fibrosis induced by UUO. The levels of intercellular adhesion molecule (ICAM)-1 and monocyte chemoattractant protein (MCP)-1 were examined to verify the role of macrophage infiltration and inflammatory injury. Co-expression of macrophage marker CD68 and myofibroblast marker -SMA to identify MMT contributing to cardiac fibrosis.

Results:

We identified cardiac injury in UUO rats, and eplerenone can inhibit UUO-induced cardiac fibrosis. We found that macrophages can co-express the myofibroblast marker alpha-SMA for phenotypic transformation and participate in cardiac fibrosis by secreting collagen III, while eplerenone inhibits this process. Activated MR enhanced macrophage infiltration and secretion of ICAM-1 and MCP-1, which stimulated inflammatory injury in the heart, whereas aldosterone stimulation and eplerenone treatment with RAW264.7 revealed a role for aldosterone in cardiac fibrosis.

Conclusions:

Our results identified the role of aldosterone in promoting macrophage infiltration and MMT through MR/SGK-1 pathway. These findings provide a new mechanism for macrophage involvement in the pathogenesis of UUO-induced cardiac fibrosis and reveal novel therapeutic targets.
PS-B04-6: FIBROBLAST GROWTH FACTOR 21 - A POTENTIAL NEW TREATMENT FOR HYPERTENSION?
Authors: Williamson Hannah M , Heagerty Anthony M , Saxton Sophie N
Published: January 2023

Objective:

Perivascular adipose tissue (PVAT) is vital in regulation of vascular tone and blood pressure. PVAT function is lost in obesity, contributing to development of hypertension. Fibroblast growth factor-21 (FGF-21) is released by PVAT and has roles in body weight regulation and glucose homeostasis, however, there have been no studies on the direct effect of FGF-21 on vascular tone.

Design and method:

Wire myography was used to measure the contractility of C57BL/6J mouse second order mesenteric resistance arteries (250 μm) in response to electrical field stimulation (EFS) prior to and following incubation with the FGF-21 analogue PF-05231023 (100 μM) for 30 minutes. PVAT was collected from the entire mesenteric bed and incubated with or without PF-05231023 for 30 minutes before stimulating with EFS. The surrounding supernatant was collected and commercially available adipokine arrays were used to characterise the PVAT secretory profile.

Results:

PF-05231023 significantly reduced the vasoconstrictor response to EFS in both PVAT intact and PVAT denuded vessels. Using adipokine arrays, PF-05231023 significantly increased adiponectin and leptin secretion from PVAT, in addition to various pro- and anti-inflammatory adipokines.

Conclusion:

FGF-21 or its analogues could present a promising therapeutic tool to lower blood pressure in hypertension via both direct effects on the vasculature, and by promoting release of other vasodilatory adipokines.
PS-B04-7: CHRYSIN AMELIORATES ISOPROTERENOL-INDUCED CARDIAC HYPERTROPHY IN RATS VIA MODULATION OF SIGNALING PATHWAYS
Authors: Verma Vipin Kumar , Meshram Sonali , Arya Dharamvir Singh
Published: January 2023

Objective:

Chrysin, a flavonoid, obtained from honey has shown to possess various pharmacological activities such as anti-oxidant, anti-apoptotic, anti-fibrotic and anti-inflammatory. Isoproterenol (ISO) induced cardiac hypertrophy involve development of oxidative stress, inflammation and fibrosis in the rats. On this basis, the present study was designed to investigate the effect of chrysin in ISO-induced cardiac hypertrophy in rats.

Design and method:

Male albino Wistar rats were divided into seven groups (n = 6): Normal, ISO-control and chrysin treatment groups (15, 30 and 60 mg/kg; p.o.), chrysin per se (60 mg/kg; p.o.) and combination group (chrysin 60 mg/kg; p.o. + losartan 10 mg/kg; p.o.). Chrysin was administered for the period of 28 days. Hypertrophy in all groups were induced by administration of ISO at the dose of 3 mg/kg; s.c. other than normal and per se groups. On 29th day, rats were anaesthetised, hemodynamic parameters were measured, blood was withdrawn and heart was excised. Heart was stored for the estimation of biochemical, histopathological, ultrastructural, and molecular studies.

Results:

Chrysin treatment for 28 days significantly improved heart to body weight ratio, normalized hemodynamic parameters, strengthen antioxidant parameters, prevented release of cardiac injury markers and attenuated pathological changes. In addition, it also reduced inflammation (decreased TNF-α, IL-6, pNF-κB/NF-κB ratio), apoptosis (increased Bcl-2 and decreased Bax, caspase-3 and PARP) and fibrosis (decreased TGF-β;/Smad) in ISO-induced hypertrophic rats. Furthermore, it also regulated the expression of various signaling pathways (MAPK, Nrf2/HO-1). All these changes were comparable to the losartan treatment group.

Conclusion:

Thus, chrysin pre-treatment prevented oxidative stress, inflammation, apoptosis and fibrosis in rats via alteration of various pathways. Hence, chrysin could be further studied for treatment of cardiac hypertrophy.
PS-B05-1: ACETATE AMELIORATES CARDIAC INFLAMMATION IN A RAT MODEL OF POLYCYSTIC OVARIAN SYNDROME BY SUPPRESSION OF PCSK9/NF-KB-DEPENDENT PATHWAYS
Authors: Areloegbe Stephanie Esosa , Olaniyi Kehinde Smuel
Published: January 2023

Objectives:

Endocrinometabolic disorders in women of child-bearing age, including polycystic ovarian syndrome (PCOS) has contributed to increased prevalence of cardiovascular disease (CVD) risk and its attendant complications, which often degenerate to cardiovascular morbidity and mortality, that is among the leading cause of death globally. Acetate, the most abundant endogenously produced short chain fatty acid has been linked to metabolic health. However, the impact of acetate on CVD-driven pathologies in PCOS is unknown. The present study therefore hypothesized that acetate would attenuate cardiometabolic abnormalities in experimentally induced rat model of PCOS, possibly by suppression of PCSK9/NF-kB-dependent pathways.

Materials and Methods:

Eight-week-old female Wistar rats were allotted into four groups (n = 6) and the groups received vehicle, acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage and lasted for 21 days.

Results:

In letrozole-induced PCOS rats characterized with insulin resistance, glucose dysregulation, elevated plasma testosterone and decreased 17-Beta estradiol as well as degenerated ovarian follicles and reduced normal follicles. There was also a significant increase in plasma and cardiac lipid/lipoproteins, lipid peroxidation, inflammatory mediators (NF-kB and TNF-alpha), gamma-glutamyl transferase/lactate dehydrogenase and lactate content, PCSK9 and reduction in plasma and cardiac antioxidants (glutathione peroxidase and reduced glutathione) and plasma nitric oxide synthesis (eNOS and NO) compared with the control rats. In addition, immunohistochemical assessment of cardiac tissue showed severe expression of inflammasome in letrozole-induced PCOS rats compared with the control rats. Nevertheless, supplementation with acetate significantly attenuated these alterations.

Conclusions:

The current study demonstrates cardiac inflammation in experimentally induced PCOS, which is accompanied by elevated atherogenic lipid/LDLc, NO-dependent oxidative stress and endothelial dysfunction and mediated by elevated levels of PCSK9 and NF-kB. The results in addition suggest that acetate attenuates PCOS-associated cardiac inflammation by suppression of PCSK9/NF-kB-dependent mechanisms.
PS-B05-5: PROTECTIVE ROLE OF ACETATE AGAINST RENAL DYSFUNCTION IN EXPERIMENTAL MODEL OF POLYCYSTIC OVARIAN SYNDROME
Authors: Badejogbin Olabimpe Caroline , Areloegbe Stephanie Eseosa , Olaniyi Kehinde Samuel
Published: January 2023

Objective:

Various endocrinometabolic diseases inclusively polycystic ovarian syndrome (PCOS), has been linked with increased risk of renal dysfunction with attendant cardiovascular disease (CVD) in women of reproductive age. Short chain fatty acids (SCFAs) especially acetate have been suggested as an immunometabolic modulator. However, the impact of SCFAs, particularly acetate on renal disorder in PCOS individuals is unknown. The present study therefore hypothesized that acetate would circumvent renal dysfunction in a rat model of PCOS.

Design and Methods:

Eight-week-old female Wistar rats were randomly distributed in four groups (n = 6), which received vehicle, sodium acetate (200 mg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage for a duration of 21 days.

Results:

Animals with PCOS displayed insulin resistance, lipid dysmetabolism, hyperandrogenism, hyperleptinemia and hypoadiponectinemia. Besides, the result also showed increased renal malondialdehyde, lactate production, inflammatory mediators, urea and creatinine levels. Immunohistochemical analysis also demonstrated severe expression of apoptosis and inflammation with BAX/NLRP3 antibodies. However, supplementation with acetate significantly attenuated these anomalies.

Conclusion:

The present results collectively suggest that acetate reverses renal dysfunction in experimentally induced PCOS animals by attenuating androgen excess, apoptosis, oxidative stress and NF-kB/NLRP3 immunoreactivity.
PS-B05-7: HYPERTENSION IN A MODEL OF PKD IS NOT DEPENDENT ON THE SHORT-TERM ACTIONS OF TUMOUR NECROSIS FACTOR-A IN THE SFO
Authors: Van Acquoy Monique L , Goodchild Ann K , Phillips Jacqueline K , Hildreth Cara M
Published: January 2023

Objective:

The development of hypertension in the Lewis polycystic kidney (LPK) disease model of kidney disease is caused, in part, by neuronal overactivity in the subfornical organ (SFO). Circulating proinflammatory cytokines, namely TNFα, are suggested to act in the central nervous system to produce an increase in neuronal excitability. As circulating cytokines are increased in kidney disease, we hypothesised that TNFα acts on the SFO to increase neuronal activity, therefore contributing to the development of hypertension in this animal model.

Design and Methods:

Urethane anaesthetised Lewis control (n = 23 total) and LPK (n = 18 total) animals were instrumented to record blood pressure and perform microinjections of TNFα (1–300pg/50nl), TNFα receptor 1 (TNFRI) neutralising antibody (1ng/50nl) or minocycline (0.5 μg/50nl), an inhibitor of microglial activation.

Results:

Exogenous TNFα microinjected into the SFO elicited a significant pressor response in the Lewis control but not the LPK animals (9 ± 2 mmHg vs -1 ± 3 mmHg, Lewis vs LPK peak change from baseline, P = 0.04). Acute inhibition of actions of local TNFα via administration of TNFRI neutralising antibody in the SFO did not reduce mean arterial blood pressure in Lewis control or LPK animals (1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.59). Acute blockade of the actions of all proinflammatory cytokines on microglia via microinjection of minocycline in the SFO did not reduce blood pressure in Lewis control or LPK animals (-1 ± 1mmHg vs -1 ± 1mmHg, Lewis vs LPK change from baseline, P = 0.11). Prior microinjection of TNFRI neutralising antibody into the SFO abolished the pressor response observed upon microinjection of TNFα in Lewis rats (9 ± 2 mmHg vs 1 ± 1 mmHg, TNFα vs TNFα after TNFRI Ab peak change from baseline, P = 0.01), whereas prior microinjection of minocycline into the SFO only attenuated the pressor response observed upon TNFα microinjection in Lewis rats (9 ± 2 mmHg vs 3 ± 1 mmHg, TNFα vs TNFα after Minocycline peak change from baseline, P = 0.04)

Conclusions:

Overall, these findings demonstrate that although hypertension observed in the LPK is sustained by an increase in SFO activity, the short-term control of mean arterial blood pressure activity is not dependent on the actions of endogenous TNFα or generalised microglial activation by proinflammatory cytokines in the SFO.
PS-B05-8: AGTR1A RECEPTORS IN NEURONS OF THE SUBFORNICAL ORGAN AND THE PARAVENTRICULAR NUCLEUS OF HYPOTHALAMUS ACTIVATE SPLENIC IMMUNITY TO HYPERTENSIVE STIMULI
Authors: Perrotta Marialuisa , Carnevale Lorenzo , Pallante Fabio , Mastroiacovo Francesco , Perrotta Sara , Fardella Valentina , Lembo Giuseppe , Carnevale Daniela
Published: January 2023

Angiotensin II (AngII) is an important modulator of the sympathetic nervous system (SNS), activating type 1a AT receptors (AT1aRs), densely expressed in brain regions controlling cardiovascular function. Circumventricular organs (CVOs) locating in proximity of the ventricles are characterized by a leaky blood brain barrier, with the subfornical organ (SFO) particularly, exposed to circulating substances like AngII. Interestingly, the SFO is structurally and functionally connected to the paraventricular nucleus of the hypothalamus (PVN), a key regulator of the SNS. In our previous works, we demonstrated that AngII is capable to increase blood pressure by recruiting the splenic sympathetic nervous system (SSNA) and adaptive immune response in mice. Whether the splenic SNS and immune response are under brain control in hypertension is still unknown.

To investigate the role of SFO, we exploited the stereotaxic injection of a recombinant adenovirus, encoding a Cre-recombinase and a GFP-reporter (AT1aR-KO-SFO), or GFP alone as control (AT1aR-WT-SFO), in the SFO of AT1aRflox mice. To selectively target AT1aRs in the PVN, we crossed AT1aRflox with mice expressing a Cre recombinase under Sim1 promoter, which typically characterize PVN neurons (AT1aR KO-PVN and AT1aR WT-PVN mice). Efficacy of gene deletion was evaluated by RT-PCR in brain samples obtained by laser microdissection (Figure 1) and AngII or vehicle were infused for 28 days through osmotic minipumps.

First, we evaluated SSNA by microneurography, finding a significant reduction in firing frequency of mice with AT1aR KO in SFO. Then we analyzed whether the SSNA inhibition also hampered immune activation in the spleen and by immunofluorescence analysis of splenic white pulp area containing CD3 T cell, we observed that AT1aR KO-SFO mice displayed a reduced egression of T cells after chronic AngII infusion from the spleen towards target organs of hypertension. Further supporting the observation that AT1aR signaling in the brain SFO are necessary to prime T cell egression from the spleen, we found a significantly reduced infiltration of CD8 and CD4 T cells, and less renal damage, typical hallmarks of hypertension. More important, we also observed that AT1aR KO-PVN mice were significantly protected from AngII-induced hypertension, when compared to their respective controls showing a protection from T cells egression and infiltration in kidneys.

Our data demonstrate the existence of a SFO-PVN-splenic axis as the main neural regulator of AngII-induced immune response and blood pressure increase.

JOURNAL/jhype/04.03/00004872-202301001-00918/figure1/v/2023-10-24T163949Z/r/image-jpeg
PS-B06-1: LOW DOSE SPIRONOLACTONE ALLEVIATES CARDIO-RENAL DISORDER IN EXPERIMENTAL PCOS RAT MODEL BY REDUCTION OF BAX/INFLAMMASOME IMMUNOHISTOCHEMICAL EXPRESSION
Authors: Peter Mmenyene Usen , Areleogbe Stephanie Esosa , Bashir Alamin Mohammed , Akintayo Christopher Oloruntoba , Oniyide Adesola Adesina , Olaniyi Kehinde Samuel
Published: January 2023

Objectives:

Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorders among women of reproductive age. It has been associated with cardio-renal disturbance. In fact, cardiovascular disease and chronic kidney disease remain the major cause of disease burden worldwide. Mineralocorticoid receptor activation has been demonstrated in various pathological conditions, including cardiovascular and renal dysfunction. Spironolactone is a mineralocorticoid receptor blocker that regulates metabolic-related functions. However, the impact of spironolactone (LSPL), on PCOS associated cardio-renal disorder is unknown. Therefore, the present study hypothesized that LSPL would ameliorate cardio-renal disorders in experimental PCOS animal.

Materials and Methods:

Female Wistar rats that were eight-week-old were allotted into three groups. The control group received vehicle (distilled water; p.o.), LET-treated group designated as PCOS group received letrozole (1 mg/kg; p.o.), while PCOS+LSPL received a combination of letrozole and LSPL (0.25 mg/kg, p.o.). The treatment was done once daily for 21 days uninterrupted.

Results:

The experimental PCOS rats were characterized with insulin resistance as well as, elevated testosterone and LH/FSH with a significant increase in cardiac and renal lipid profile, oxidative stress, inflammatory biomarkers (NF-kappaB and TNF-alpha), LDH and lactate content, and decrease in cardiac and renal antioxidant system (GPX and GSH) compared with the control rats. There was also a significant increase in cardiac GGT but not renal GGT activity in PCOS animals. In addition, immunohistochemical assessment of cardiac and renal tissue showed severe expression of inflammasome and moderate expression of BAX in animals with PCOS. Nevertheless, these perturbations were attenuated following the administration of LSPL.

Conclusion:

Collectively, the present results suggests that low dose spironolactone attenuates PCOS-associated cardio-renal disorders by reduction of oxidative stress and BAX/Inflammasome expression.
PS-B06-3: SEX-SPECIFIC EFFECTS OF IMMUNOSUPPRESSANTS ON SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Maranon Rodrigo O , Reckelhoff Jane F , Moulana Mohadetheh
Published: January 2023

In the last decade, the role of immunosuppression in hypertension has been under discussion. However, whether there is a sex-dependent response to immunosuppressants had not much attention.

Aim:

To evaluate the sex differences in tacrolimus and mycophenolate mofetil (MMF) response in young female (YF) and male (YM) spontaneously hypertensive rats (SHR) and whether T cells contribute to mean arterial pressure (MAP) changes.

Main Methods:

YF and YM SHR received either tacrolimus or MMF for 14 days. Rats were implanted with radiotelemeters, MAP was measured chronically, then circulating and renal infiltrated CD4+, CD8+, Th17, and T regulatory (Treg) T cells were quantified using flow cytometry.

Results:

Tacrolimus increased MAP only in males and decreased circulating CD4+ and CD8+ T cells in both YM (30% and 38%) and YF (30% and 72%), respectively; being CD8+ more affected in females (p < 0.05). Also, Tacrolimus reduced renal CD4+ and Treg cells more in YM. MMF reduced MAP, circulating, and renal CD4+ and CD8+ T cells in YM and YF. Also, MMF decreased Th17 and Treg cells in both, but the decrease in Th17 was higher in males (p < 0.05), and the reduction in Treg cells was higher in females (p < 0.05).

Conclusion:

Targeting T cells in hypertension using immunosuppressants may have different effects on men and women, and hypertension management by immunosuppressive therapy and post-transplant hypertension should be specified by gender.