bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P216: Distal Convoluted Tubule-Specific Deletion of Specific Deletion of (Pro)Renin Receptor in Mice Increases Energy Expenditure and Enhances Aggressiveness
Authors: Zheng Huaqing , Lambert Jacob , Wang Fei , McCormick James , Kaewsaro Kannaree , zou Changjiang , Yang Tianxin
Published: October 2024

Our previous study suggested a potential role of (pro)renin receptor (PRR) in the regulation of Na
+
-Cl
-
cotransporter (NCC) activity in the distal convoluted tubule (DCT). Here, we employed
Slc12a3
-CreERT2 to generate inducible DCT-specific deletion of PRR in mice (KO). As expected, the KO mice exhibited a 1.8-fold increase in renal NCC activity as reflected by HCTZ-induced natriuresis. Surprisingly, the KO mice developed metabolic and behavioral phenotypes. By calorimetry, 4-month-old male KO mice exhibited an enhanced energy expenditure as compared with floxed controls (oxygen consumption: 4172.5 ± 118.0 ml/kg/hr
vs.
3303.5 ± 69.8 ml/kg/hr; CO
2
consumption: 3617.3 ± 87.8 ml/kg/hr
vs.
2784.2 ± 58.5 ml/kg/hr; heat production: 20.4 ± 0.6 Kcal/kg/h
vs.
16.2 ± 0.8 Kcal/kg/h, n = 5-9,
p
< 0.01), accompanied by enhanced locomotor activity (by 41.3%) and reduced body weight (30.2 ± 0.5 g
vs.
28.0 ± 0.3 g, n = 5-9,
p
< 0.05). The changes in locomotor activity were confirmed by using radiotelemetry. Additionally, resident-intruder aggression test demonstrated that under basal condition, the KO mice exhibited a higher aggression rate as compared with floxed controls (80% in KO group
vs
. 30% in floxed group, n = 10). The KO mice also exhibited shorter clinch attack latencies, higher number of attacks and attack duration (attack latencies: 79.0 ± 17.6 s in KO group
vs
. 172.5 ± 5.3 s in floxed group; attack frequency: 3.4 ± 0.8 in KO group
vs
. 0.7 ± 0.4 in floxed group; attack duration: 10.1 ± 2.0 s in KO group
vs
. 1.1 ± 0.6 s in floxed group, n = 10,
p
< 0.01). Furthermore, the KO mice exhibited elevated plasma level of Klotho (321.4 ± 16.3 pg/ml in KO group
vs.
254.1 ± 9.8 pg/ml in floxed group, n = 11-12,
p
< 0.01) that is known to promote energy expenditure in addition to its cardiorenal protective actions. In cultured renal HK2 cells, recombinant soluble PRR (sPRR-His) downregulated Klotho mRNA and protein expression by 29.8% and 37.9%, respectively. Overall, the present study uncovered a novel role of DCT PRR in the regulation of energy metabolism and behavior, part of which may be mediated by antagonism of Klotho action.
Abstract P221: Yoda2, a Novel Piezo1 Agonist, Induces Relaxation in Mouse Vascular and Corpus Cavernosum Tissues
Authors: DosAnjos Moraes Raiana , Vieira dos Santos Cintia , Rodrigues dos Passos Rinaldo , Tomazini Goncalves Tiago , Webb R Clinton , Priviero Fernanda
Published: October 2024

Introduction:
Piezo1, a mechanosensitive nonselective cation channel, is expressed in endothelial and vascular smooth muscle cells. It plays a critical role in sensing endothelial shear stress, generating nitric oxide (NO), regulating vascular tone, promoting angiogenesis, and controlling blood pressure. Yoda1, a tool compound for Piezo1, has limitations due to its low potency and poor water solubility. To overcome these limitations, a Yoda1 analogue, Yoda2, was developed. Yoda2 features a 4-benzoic acid moiety replacing the pyrazine of Yoda1, thereby enhancing its agonist properties and solubility. We hypothesize that Yoda2 induces relaxation in mouse mesenteric resistance artery (MRA), pudendal artery (PA), and corpus cavernosum (CC), through a NO-dependent mechanism.

Methods:
Male C57BL/6 mice were euthanized, and their MRA, PA, and CC were isolated and mounted in DMT wire myographs for isometric force measurements. Concentration-response curves to Yoda2 were obtained. Additionally, the contraction of CC induced by electrical field stimulation (EFS) was evaluated in the absence or presence of Yoda2. Data are presented as mean ± S.E.M of 3-4 mice. Non-linear regression curve was performed, and the maximum response (E
max
) and pharmacological potency (pEC
50
) were analyzed using Student's t-test (p<0.05).

Results:
Yoda2 induced concentration-dependent relaxation in the MRA, PA, and CC, with E
max
values of 98.31 ± 0.89% for MRA, 95.01 ± 3.75% for PA, and 75.03 ± 15.17% for CC. The role of NO in this pathway was confirmed by the attenuation of Yoda2 effects upon inhibition of NO synthase (NOS) with L-NAME in MRA and PA. Furthermore, Yoda2 (1 µM) decreased the concentration response curves for phenylephrine-induced contraction in PA and MRA. On the other hand, Yoda2 (30 µM) did not change the EFS-induced contraction in CC.

Conclusion:
This study is the first to demonstrate that Yoda2, a potent and water-soluble Piezo1 channel agonist, induces significant relaxation in the MRA, PA, and CC of mice. Consistent with the effects of Yoda1, the effects of Yoda2 are mediated through NO production.
Abstract P223: Impact Of Dynamic Or Static Training On Flow-Mediated Dilatation Following Prolonged Head-Down Tilt Bedrest
Authors: Kloesges Lukas , Hoenemann Jan , Hoffmann Fabian , Bechler Sophie , Timmermans Finn , De Boni Laura , Gauger Peter , Mulder Edwin , Moestl Stefan , Heusser Karsten , Odainic Alexandru , Schmidt Susanne , Schmitz Marie-Therese , Heise Tim , Halbach Marcel , Baldus Stephan , Laurie Steve , Lee Stuart , Macias Brandon , Jordan Jens , Tank Jens
Published: October 2024

Cardiovascular deconditioning, cephalad fluid shifts, and altered sympathetic activity in weightlessness may elicit changes in vascular structure and function akin to vascular ageing. Head-down tilt bedrest is an established terrestrial model for weightlessness and elicits similar cardiovascular responses. We hypothesized that 30 days head-down tilt bedrest (HDTBR) worsens flow mediated dilation (FMD), a non-invasive endothelial function marker, and that daily orthostatic stimuli or physical exercise attenuates the response.

Fourty-seven healthy individuals (20 women, age 35±9 years, BMI 23.7±2.6 kg/m
2
) were assigned to 30 days of strict HDTBR and divided into four groups: Daily 6 hours of upright sitting (positive control, n=11); 6 hours of -25 mmHg lower body negative pressure (n=12); 60 minutes of supine cycling followed by 6 hours of thigh cuff venous occlusion 6 days per week (n=12), or no countermeasure (negative control, n=12). We measured upper arm blood pressure and heart rate 5 days before and immediately after bedrest. We assessed plasma volume by carbon monoxide-rebreathing 2 days before and on day 28 of bedrest. We determined FMD of the brachial artery 5 days before, on day 28 of bedrest, and after 13-day recovery. We collected blood samples to measure pro- and anti-inflammatory cytokines.

Heart rate was elevated after bedrest (p<0.0001) but remained constant in seated and cycling groups (seated MD 5±2 /min, cycling MD 5±2, p=0.0051). Systolic blood pressure increased in all groups (MD 4±1 mmHg, p=0.0004). Diastolic blood pressure was higher post-bedrest in the control group (MD 8±2 mmHg, p=0.0002) but remained constant in the countermeasure groups. Plasma volume was reduced after bed rest (MD -400±37 ml, p<0.0001) but maintained in the cycling group (MD 147±72 ml, p=0.0001). FMD did not differ between groups, but was higher at bedrest (MD 1.9±0.8 %, p=0.0481), whereas recovery values did not differ from baseline. Resting brachial artery diameter tended to be higher at bedrest (p=0.0876). Cytokines revealed no clinically relevant inflammatory response.

Head-down tilt bedrest-induced cardiovascular deconditioning, which was not completely abolished by any countermeasure, paradoxically increased flow-mediated brachial vasodilation. Additional cardiovascular risk factors may be required to express endothelial dysfunction in the face of reduced physical activity.
Abstract P231: Self-administration of Remifentanil Induces Endothelial Dysfunction in Thoracic Aorta and Impaired Cavernosal Reactivity of Wistar Rats
Authors: Townsend Paul , Watson Jacob , Vieira Cintia , Bomfim Gisele , Rodrigues Rinaldo , Silva Carla , Harrod Steven , Vento Peter , Webb R Clinton , Priviero Fernanda , Wenceslau Camilla
Published: October 2024

Aims:
Recent studies have implicated the use of prescription opioids as a risk factor for cardiovascular diseases (CVD), with associations including myocardial infarction, coronary artery disease and vascular deterioration. Further, opioid-dependent patients show increased vascular aging and arterial stiffness when compared to opioid-naïve controls. Our hypothesis was that rats dependent on remifentanil (a fentanyl analog) after a 12-day operant self-administration (SA) study lead to vascular dysfunction in thoracic aorta. Because erectile dysfunction (ED) is associated with arterial stiffness and is positively correlated with its severity, we hypothesized that opioid SA impaired corpus cavernosum (CC) reactivity as well.

Methods:
Male Wistar rats (12 weeks-old) were implanted with intravenous catheters and learned to lever press (FR1) for remifentanil (1µg/kg/infusion). A separate group of rats received passive yoked infusions of saline administered in synchrony with remifentanil-treated animals to control volumetric vascular effects. Following administration, animals were euthanized, and aorta and CC collected to evaluate function using both pin and strip myographs. Concentration-response curves to phenylephrine (Phe; 10
-11
-10
-4
M), sodium nitroprusside (SNP) and acetylcholine (Ach or SNP; 10
-10
-10
-4
M) were performed to test contractility and endothelium-independent and -dependent relaxation respectively.

Results:
Remifentanil-treated rats showed rapidly acquired SA behavior, exhibiting robust and selective drug-paired lever pressing when compared to the non-drug paired lever. In contrast, yoked saline-treated controls rarely exhibited lever pressing. Endothelium-dependent relaxation in the aorta was diminished in the remifentanil group (Rmax: Control: 68.7±2.7
vs.
Remi: 47.8±3.7%; p<0.05). There were no observed alterations in endothelium-independent relaxation or vascular contraction. However, CC contraction was slightly shifted to the right in remifentanil treated rats (pEC
50
: Control: 6.04±0.09
vs.
Remi: 5.66±0.12; p<0.05). No changes were observed in the CC relaxant response. These findings indicate that 12 days of remifentanil administration results in endothelial dysfunction in large arteries and impaired cavernosal reactivity. Long-term exposure may lead to aortic stiffness exacerbating ED severity and increases in pulse-wave velocity in opioid-dependent patients contributing to the onset of hypertension.
Abstract P306: Aldosterone levels are associated with hypertension in post-menopausal women: the Study of Women’s Health Across the Nation
Authors: Byrd J Brian , Leis Aleda , Hood Michelle , Dhar Shichi , Rao Satish , El Khoudary Samar , Thurston Rebecca , McConnell Daniel , Auchus Richard , Karvonen-Gutierrez Carrie
Published: October 2024

Introduction:
Hypertension (HTN) is the leading cause of premature death in women. Apparent treatment-resistant hypertension (aTRH) is systolic blood pressure (SBP) ≥140 or diastolic BP (DBP) ≥90 mmHg despite treatment with ≥3 antihypertensive medications, or the use of ≥4 antihypertensive medications (irrespective of the BP level). aTRH occurs in approximately 17% of people with treated HTN. High aldosterone may elevate cardiovascular risk; despite causing sodium retention, aldosterone may paradoxically continue to be secreted even when dietary sodium intake is high. Little is known, however, about how aldosterone relates to BP and HTN in women, in whom significant increases in BP, carotid atherosclerosis, and arterial stiffness occur near the time of menopause. We examined the relationships of aldosterone with HTN and aTRH in a cohort of post-menopausal women.

Methods:
The Study of Women’s Health Across the Nation (SWAN) is a longitudinal cohort of women followed from midlife into late adulthood. This cross-sectional analysis included 999 women (30.3% of the cohort) free of congestive heart failure and with serum aldosterone measured during the 2015-2016 (15th follow-up) study visit. HTN was defined as SBP or DBP ≥140 or ≥90 mmHg, respectively, or use of antihypertensive medications. aTRH was defined as reported use of 4 or more concurrent antihypertensive medications at any visit, or 3 or more concurrent medications and SBP≥140 or DBP≥90 at two consecutive visits. Multivariable logistic regression related HTN or aTRH and aldosterone, adjusting for age, race/ethnicity, and body mass index.

Results:
In this cohort of women [mean age 66 years (standard deviation:2.7)], the prevalence of HTN and aTRH was 52% and 4.1%, respectively. Women with aTRH had higher median serum aldosterone [8.7 ng/dL, interquartile range (IQR) 5.0-11.7] versus those without (6.7 ng/dL, IQR 2.7-10.5). Each unit increase in aldosterone was associated with a 4% increased odds of HTN (95%CI 1.02,1.06; p<0.001). Similarly, the odds ratio for aTRH in the adjusted model was 1.04 (95%CI 0.99,1.08), although the association was not statistically significant (p=0.09).

Conclusion:
Aldosterone was positively associated with HTN and there was a non-statistically significant trend toward an association with aTRH in this cohort of post-menopausal women. Our findings suggest that aldosterone within an ostensibly “normal” range is associated with HTN in postmenopausal women.
Abstract P310: Subclinical primary aldosteronism is associated with an increased risk of major adverse cardiovascular events
Authors: Merabtine Amel , Hundemer Gregory , Madore Francois , Agharazii Mohsen , Goupil Remi
Published: October 2024

Background:
Subclinical primary aldosteronism (PA), defined as renin-independent aldosterone production without overt PA, has recently been associated with adverse cardiac remodelling, unfavorable indices of arterial stiffness and incident hypertension. The objective of this study was to evaluate whether subclinical PA is linked to an increased risk of cardiovascular events.

Methods:
This study used data from CARTaGENE, a populational cohort of randomly selected individuals aged 40-69 years, with prospective outcomes data obtained from linkage with governmental administrative databases. The outcome of interest was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, stroke and heart failure, assessed from enrollment (2009-2010) to March 2021. All individuals with available plasma renin and aldosterone measurements, outcomes data and nutritional assessment were included in this study. Cox regression models were used to test the associated between MACE and the log-transformed aldosterone-to-renin ratio (ARR), with adjustments for sex, age, height, weight, race, diabetes, prior cardiovascular disease, smoking status, systolic BP, heart rate, estimated glomerular filtration rate, sodium and potassium levels, LDL- and total-cholesterol, antihypertensive drugs (listed as individual classes), statin and aspirin use, and 24-hour nutritional intake of sodium and potassium. Multiple imputation was used for missing data.

Results:
In 2,055 participants with available data (45.5% female, mean age 55.6 years, 6.6% diabetes, 2.9% prior cardiovascular disease, mean baseline systolic BP 128.5 mmHg), 58 MACEs occurred over a median follow-up of 10.8 years (IQR 10.6-11.0). In the Cox regression analysis, the log-transformed ARR was predictive of MACE with a hazard ratio (HR) of 2.86 (95% CI 1.34 to 6.10, p=0.007). Results were similar when participants taking any anti-hypertensive drug were excluded (HR 3.05, 95% CI 1.38 to 6.71, p=0.006).

Conclusion:
In a representative sample of the general population, a higher ARR appears to be highly predictive of adverse cardiovascular events. This indicates that subclinical PA could be an important and yet unrecognized risk factor for cardiovascular diseases, and may warrant screening in a broader population.
Abstract P317: Are Home Blood Pressure Devices Accurate? A Systematic Review of the Evidence
Authors: Hiremath Swapnil , Sterling Brayden , Glassman Isaac , Ruzicka Marcel
Published: October 2024

Background:
Out of office blood pressure (BP) measurements, especially home BP monitoring, are recommended for diagnosis and management of hypertension by all professional societies and guidelines. Though validation protocols exist for individual monitors, little data exists on the real world accuracy of home BP monitors, in actual use. We undertook this systematic review to estimate the accuracy of home BP monitors as reported in the literature.

Methods:
We undertook a literature search of MEDLINE and EMBASE from 1946 and 1947 until April 2023 respectively. We included studies that evaluated the accuracy of home BP devices against manual BP considered as the gold standard. Two reviewers independently selected studies, extracted data and assessed quality. Disagreements between the two reviewers were resolved by a third author.

Results:
Our search revealed 1284 non-duplicate citations. After applying selection criteria, nineteen studies, involving 4954 patient-devices (median 91, interquartile range 69, 489) were included in the systematic review. The reported inaccuracy of home BP monitors compared to mercury sphygmomanometer ranged from 10% to 72% for systolic BP, with each study using different thresholds for inaccuracy. The absolute mean difference for systolic BP between home BP monitor and the standard ranged from 2.4 mm Hg to 10.4 mm Hg and for diastolic BP from 1 to 8.7 mm Hg.

Conclusion:
The existing literature reports a relatively high degree of inaccuracy in home BP monitors being used. Data is limited by varying definitions being used for reporting inaccuracy. Consideration should be given to standardised definitions of accuracy, and individual patient validation of accuracy as home BP monitors use for clinical decision making becomes widespread.
Abstract P320: Novel Pulse Waveform Index Obtained by Ambulatory Blood Pressure Monitoring is Associated with Echocardiographic Ejection Fraction in Patients with Heart Failure
Authors: Narita Keisuke , Yuan Zihan , Yasui Nobuhiko , Hoshide Satoshi , Kario Kazuomi
Published: October 2024

Introduction:
Simple, non-invasive assessment of cardiac function is useful in the management of heart failure (HF).

Hypothesis:
We hypothesized that pulse waveform analysis from oscillometric cuff blood pressure (BP) measurement can estimate cardiac function. The aim of this study is to investigate the association of the pulse waveform index we developed from ambulatory BP monitoring, which represents cardiac systolic function in the ambulatory setting, with echocardiographic left ventricular ejection fraction (LVEF) in patients with HF.

Methods:
A cuff volumetric waveform was obtained from the diastolic phase of each BP measurement with a multisensor ABPM (TM-2441, A&D). The area of the ejection portion is the square forward pulse wave (Sf), which is related to the cardiac ejection. The amplitude (Am) of the waveform represents arterial and cuff compliance. Sf is divided by Am, i.e., Sf/Am, to eliminate the effect of arterial and cuff compliance, which represents left ventricular systolic function (
Figure)
.

Results:
Patients with HF who were clinically stable in the inpatient or outpatient setting (n=195) underwent both measurements of the multisensor-ABPM and echocardiography. LVEF was determined by the modified Simpson’s method. Patient characteristics were as follows: mean age, 72.1±14.7 years; male, 57%; and atrial fibrillation (AF), 39%. Sf/Am was associated with LVEF (r=0.44, p<0.001) (
Figure
). This association was also significant in the multivariable linear regression model including age, sex, body mass index, use of HF medications, coronary artery disease, and AF (β=0.43, p<0.001).

Conclusions:
Sf/Am, which is obtained by ABPM, is associated with echocardiographic LVEF.
Abstract P321: Team-Based Care: A Winning Strategy for Managing Hypertension
Authors: Sherpa Mingma , Anand Renata
Published: October 2024

Hypertension is a serious health condition that can lead to heart disease. Despite available methods for managing hypertension, blood pressure (BP) control in the US is declining, highlighting a gap between expert recommendations and real-world practice. Our clinic initiative aimed to create a specialized workflow and team, which included resident physicians, pharmacists, and health counselors focused on underserved communities. We also provided blood pressure cuffs and encouraged patients to monitor their blood pressure at home. This approach, coupled with the 'Knowing Your Numbers' campaign, has significantly improved outcomes, promoted continuity of care, and built resilience within care communities for vulnerable populations.

110 patients with poorly controlled hypertension were provided with BP monitors to track their blood pressure. Demographic data and office BP readings before and after the monitors were distributed were collected from patient charts. The results were analyzed using descriptive statistics and paired t-tests.

The study included 58% female participants with an average age of 59. The racial distribution was 51% black, 35% white, 10% unreported/unknown, 2% Asian, and 2% American Indian/Alaska native. Most participants (70%) reported feeling empowered in their healthcare. Female participants who received a blood pressure cuff and engaged in shared decision-making experienced a significant reduction in their systolic BP by 17.6 mm Hg (P<0.05) and diastolic BP by 7.9 mm Hg (P<0.05). In comparison, males saw a reduction in their systolic BP by 10.6 mm Hg (P<0.05) and diastolic BP by 7.1 mm Hg (P<0.05). The average weight for both genders falls under the obese category, with females having an average BMI of 32.4 and males having an average BMI of 32.6.

Providing loan-free blood pressure monitoring cuffs for clinic patients or blood pressure machines through insurance can improve patient engagement and health outcomes. Removing cost barriers can significantly impact in-office blood pressure reduction, monitoring, and patient satisfaction. This initiative highlights the importance of implementing patient-centered approaches to healthcare that address the financial and logistical barriers that can hinder effective hypertension management. Future research is needed to confirm these findings, but this study supports implementing similar programs to improve patients' health and well-being.
Abstract P332: High Shared Decision-Making Scores Associated with Blood Pressure Control: The Office Guidelines Applied to Practice (Office-GAP) IMPACT Program
Authors: Woodhams William , Jones Kyle , Martz Matthew , Uwaje Chucks , Efeovbokhan Nephertiti , Luo Zhehui , White-Perkins Denise , Kelly-Blake Karen , Hart-Davidson William , Olomu Adesuwa
Published: October 2024

Introduction:
Cardiovascular disease (CVD) mortality is higher in people with diabetes mellitus due to the increased prevalence of CVD risk factors. The Office-Gap IMPACT Program (Office-Guidelines Applied to Practice Improving Diabetic Patients’ Adherence to Treatment and Prevention of Cardiovascular Disease) is a patient activation cluster-randomized trial (intervention: Office-GAP + text vs. control: text alone) seeking to improve communication and patient-provider partnerships through patient and provider training in shared decision-making (SDM), use of a guideline-based checklist, and text messaging to improve medication adherence in Federally Qualified Health Care Centers.

Hypothesis:
We assessed the hypothesis that individual level demographic and clinical characteristics of patients enrolled in Office-GAP IMPACT would be associated with patient-reported SDM using the CollaboRATE 3-item instrument, which measures three core SDM domains: (1) explanation of health issues, (2) elicitation of patient preferences and (3) integration of patient preferences into decisions with a 10-point response scale for each domain ranging from 0 “No effort was made” to 9 “Every effort was made.”

Methods:
The CollaboRATE was completed three months after baseline. A top-scoring method (a rating of 9 for all three items) was used to dichotomize CollaboRATE responses into two categories - participants who reported the highest levels of SDM on each of the three items versus those who did not. Accounting for the cluster-randomized design, generalized estimating equations (GEEs) were used to compare demographics and baseline factors that may be associated with the outcome.

Results:
A total of 288 patients were enrolled (intervention, N=158 and control, N=130). Among those with non-missing CollaboRATE scores, 152 (73% ± 3%) had high SDM. The inverse probability of non-missing weighting method was used to account for the missing data in CollaboRATE. Results from the weighted univariable models suggested older patients, history of smoking, and those with BP under control (< 140/90 mmHg) at baseline were more likely to be satisfied with the SDM process. In multivariable logistic regressions, only BP control was statistically significant after adjusting for other factors.

Conclusions:
In conclusion, participants with BP control had higher SDM scores, which could lead to better health outcomes. Providers should include the practice of SDM principles in every clinical encounter.
Abstract P337: Impact of a population health approach using smartphone-enabled home albuminuria testing to improve screening in patients with hypertension or diabetes
Authors: Zafar Waleed , Hu Yirui , Brubaker Lauren , Green Jamie , Chang Alexander
Published: October 2024

Background:
Screening for albuminuria with urine albumin/creatinine ratio (ACR) testing among at risk patients is critical as guideline-based therapies can be used to decrease the risk of cardiovascular and kidney disease. However, adherence to testing remains very low, especially for hypertension. Here, we report the results from a prospective pilot study involving a smartphone-enabled home albuminuria testing quality improvement.

Methods:
We randomly selected 4000 adult individuals (50% with hypertension but no diabetes and 50% with diabetes +/- hypertension) receiving primary care at a large healthcare system in Central and Northeastern Pennsylvania who had not undergone ACR testing in the past 12 months to receive Minuteful Kidney, an FDA-cleared, smartphone-enabled home urine albuminuria screening kit using the vendor’s (Healthy.io) standard workflow. The home testing group was matched 1:1 to 4000 controls who received usual care using propensity score matching addressing imbalances in sociodemographics and comorbidities. The primary outcome was completion of ACR test (either laboratory based ACR or Minuteful Kidney) within 100 days of the index date. Results shown are as of May 1, 2024 (86 days after the index date).

Results:
Overall, completion of any ACR test was higher in the home testing group than matched controls (50.2% vs. 19.1%; p<0.001). The impact on ACR testing was higher for the hypertension subgroup (50.4% vs. 11.2%; p<0.001) than the diabetes subgroup (49.9% vs. 26.9%; p<0.001). Among the home testing group, 1542/4000 (38.7%) completed the smartphone ACR test, with a higher proportion of completions in non-diabetic hypertension (848/2000 [42.4%] than the diabetes subgroup (663/2000 [33.2%]). Adherence rates were similar across age groups and geographic location. Satisfaction was high among individuals in the home testing group (53+ Net Promoter Score; 94% rated the test as easy or very easy to complete; 88% stated preference for at home testing). Home-based albuminuria screening detected mild to moderate albuminuria (30-300 mg/g) in 33.2% and severe albuminuria (>300 mg/g) in 8.1%. Abnormal results were fairly similar for the diabetes subgroup (33.8% 30-300 mg/g, 10.8% >300 mg/g) and the hypertension subgroup (32.6% 30-300 mg/g, 5.9% >300 mg/g).

Conclusions:
A population health approach using smartphone-enabled home albuminuria testing is effective in increasing albuminuria screening among individuals with hypertension or diabetes.
Abstract P346: Expansion of meningeal lymphatic vessels in DOCA-salt hypertension
Authors: Sobanko Melissa , Santisteban Monica
Published: October 2024

The meningeal lymphatic system is critical for proper brain waste clearance and maintenance of the local meningeal neuroimmune niche. Meningeal lymphatic function is impaired during aging and neurodegenerative diseases and is associated with the development of cognitive impairment. There is a bidirectional communication between meningeal lymphatic function and dural T cells, whereby the drainage of T cells into the deep cervical lymph nodes depends on functional lymphatic vessels, and meningeal lymphatic function is itself modulated by T cell derived cytokines. We have previously shown that IL-17A producing T cells accumulate in the dura during deoxycorticosterone acetate (DOCA)-salt hypertension and contribute to the impairment of neurovascular coupling and cognitive function. However, the mechanisms by which these T cells accumulate in the dura remain to be determined. Here, we tested the hypothesis that the meningeal lymphatic vessels are impaired during DOCA-salt hypertension, thus contributing to dural T cell accumulation. 12-week old C57BL6 male mice were implanted with a s.c. DOCA pellet and received 0.9% NaCl in the drinking water for 21 days (n=4). Control mice underwent a sham surgery (n=4). Blood pressure was monitored by tail-cuff plethysmography. Meningeal lymphatic vessels were assessed by immunohistochemistry using the lymphatic vessel marker LYVE1. In a separate group of mice, we assessed meningeal lymphatic function by delivering Alexa647-Ovalbumin or IgG-RPE into the cisterna magna and measuring fluorescence in the deep cervical lymph nodes one hour after injection. DOCA-salt mice developed increased systolic blood pressure (control: 117.7 ± 4.9 vs DOCA: 141.5 ± 2.9mmHg). We observed no difference in the CD31+ dural sinus area between control and DOCA-salt (control: 11.482 ± 0.718 vs DOCA: 11.816 ± 0.662 mm
2
). We found a significant increase in LYVE1+ area surrounding the dural sinuses in DOCA-salt (control: 0.508 ± 0.039 vs DOCA: 0.816 ± 0.105 mm
2
; p=0.0329 by unpaired two-tailed t-test) and an increase in LYVE1+/CD31+ % area (control: 4.476 ± 0.462 vs DOCA: 6.840 ± 0.609 %; p=0.0213 by unpaired two-tailed t-test) which was not different between the sagittal sinus or the transverse sinus. Contrary to our hypothesis, our data suggests that the meningeal lymphatic vessels are expanded, not retracted, during DOCA-salt hypertension. The interaction between meningeal lymphatics and dura immunity in hypertension remains to be determined.
Abstract P352: Transcriptomic Effects of Prolonged Diet-Induced Obesity in Subtypes of Agouti-Related Peptide Neurons of the Hypothalamic Arcuate Nucleus
Authors: Wagner Valerie , Muskus Veitia Patricia , Sigmund Curt , Nakagawa Pablo , Grobe Justin
Published: October 2024

Obesity is the greatest impediment to improving cardiovascular health. Despite many methods to lose weight, few people can keep it off in the long-term. The adaptation (suppression) of resting metabolic rate (RMR) appears to mediate weight re-gain after weight loss, yet the neurobiology that controls RMR remains unclear. Previously we published that the angiotensin II type 1 receptor (AT
1
R/
Agtr1a
) within Agouti-related peptide (AgRP/
Agrp
) neurons of the arcuate nucleus of the hypothalamus (ARC) is critical for integrative control of RMR. In the ARC, AT
1
R is only expressed by a subset of AgRP neurons (“Type 1”). In lean animals, AT
1
R inhibits this cell via a β-arrestin-1/Gαi-coupled cascade ("Type 1i”). Prolonged diet-induced obesity (DIO) causes RMR adaptation and is associated with a spontaneous G protein cascade switch by AT
1
R in the Type 1 neuron, in which AT
1
R activation begins stimulating the cell via the Gαq-coupled cascade (“Type 1s”). Our ongoing work aims to clarify the molecular mechanisms that govern AT
1
R coupling to Gαi versus Gαq within Type 1 AgRP neurons. First, using a dual-reporter mouse with tdTomato in AT
1
R-expressing cells plus green fluorescent protein in somatostatin (SST/
Sst
)-expressing cells, we confirmed that SST expression is a selective marker of the Type 1 subtype of ARC AgRP neurons. Second, we reanalyzed our previously published single-nucleus RNA sequencing dataset describing the mouse ARC following prolonged DIO (PMC7347451) to explore the effects of DIO upon the transcriptomic profiles of AgRP neuron subtypes. Of 26 cell types initially identified, one cluster strongly expressed both
Sst
and
Agrp
(Cluster 5). Sub-clustering of Cluster 5 identified four cell types with strong
Agrp
expression (subclusters 0, 2, 5, and 6). Subcluster 6 may represent the Type 1i subtype due to high
Sst
expression, as well as enrichment for signatures of
Gαi signaling events
. Subcluster 6 also had very few DIO-induced differentially expressed genes (up=3, down=2). Interestingly, Subcluster 2 was comprised almost exclusively of nuclei from the DIO group (95%). Subcluster 2 was more closely related to Subcluster 6 than the other
Agrp
subclusters in the cluster phylogenetic tree, leading us to hypothesize that this cluster represents the DIO-induced Type 1s subtype. These data identify novel markers of AgRP neuron subtypes within the ARC, and a possible transcriptomic signature of subtype switching induced by prolonged DIO.
Abstract P355: Multiomic Analyses Reveal Sex-specific Mechanisms Governing Cardiac Fibrosis.
Authors: Farrugia Gabriella , Harper Rebecca , Krstevski Crisdion , Lelliott Patrick , Hsu Ian , Dona Malathi , Harrison Thomas , Kiriazis Helen , Donner Daniel , Pinto Alexander
Published: October 2024

Cardiac fibrosis—the deposition of excess extracellular matrix in the heart—occurs during pathological cardiac remodelling and precedes cardiac dysfunction and heart failure. Experimental and clinical data show that both cardiac fibrosis and heart failure exhibit sex-specific differences, particularly in the absence of ischemic injury. However, no study to date has systematically examined this, or the hormonal mechanisms driving these differences, using high-resolution single-cell and spatial omics.

To address this gap, we applied single-cell and spatial omics to map the quality and distribution of non-ischemic cardiac fibrosis in human and mouse hearts. Further, to query the impact of sex hormones on cardiac fibrosis development, we analysed hearts of castrated (CAST) and ovariectomized (OVX) mice, which were ectopically infused with angiotensin-II (AngII).

Using single cell transcriptomic data of hypertensive mouse hearts, we identified a fibroblast population driving cardiac fibrosis with a unique gene signature. We confirmed the presence of these cells in multiple mouse models and aged donor human hearts. Spatial mapping of fibrosis showed a sex-specific distribution of fibrosis, specifically in the development of perivascular fibrosis in the heart. Hypertensive male mice exhibited extensive perivascular fibrosis, and coronary artery adventitial hypertrophy, which was absent in females. However, OVX resulted in the development of perivascular fibrosis in hypertensive mice suggesting a cardioprotective role of estrogen. Confirming these observations, spatial transcriptomic analyses showed distinct fibrotic signatures driving perivascular and interstitial fibrosis, and transcriptomic differences between females and males. Our findings provide fundamental new insights towards the importance of biological sex in driving cardiac fibrosis, pointing to new mechanisms that may be manipulated to ameliorate development of heart failure.
Abstract P358: Interaction of Cytochrome P450 (CYP) 4A10 and CYP1B1 in the Paraventricular Nucleus in the Angiotensin II-induced Hypertension and Neuroinflammation in Female Mice
Authors: Song Chi Young , Shin Ji Soo , Lee Elaine , Malik Kafait
Published: October 2024

We have shown that 17β-estradiol (E2)-cytochrome P450 (CYP) 1B1 and catechol-ο-methyltrasnferase-generated metabolite 2-methoxyestradiol (2-ME) in the paraventricular nucleus (PVN) protects against angiotensin (Ang) II-induced hypertension and neuroinflammation. This study was conducted to determine the relationship between CYP4A10 that is expressed in the PVN and metabolizes arachidonic acid (AA) into prohypertensive eicosanoid, 20-hydroxyeicosatetraenoic acid (20-HETE), and CYP1B1 in Ang II-induced hypertension, neuroinflammation, and reactive oxygen species (ROS) production in female mice. Systemic Ang II infusion (700 ng/kg/min, s.c., two weeks) and transduction in the PVN with adenovirus (Ad)-GFP scrambled (Scr)-short hairpin (sh) RNA (200 nL bilaterally, 6.4×10
11
pfu/mL, single injection) produced a significant increase in systolic blood pressure (SBP, tail-cuff) at Day 12 compared to Day 0 (mmHg, 114±3 vs 151±3 respectively, P<0.05, n=6/group) in wild-type (WT) and a much larger increase in CYP1B1 knockout (KO) female mice having E2 but not 2-ME (119±4 vs 173±6 respectively, P<0.05, n=5/group). Ad-GFP-CYP4A10 shRNA (200 nL bilaterally, 1.0×10
12
pfu/mL, single injection) but not Ad-GFP Scr-shRNA transduced in the PVN diminished Ang II-induced increase in SBP at Day 12 in WT mice (mmHg, 119±2 vs 122±3 respectively, P<0.05, n=5/group), and CYP1B1KO mice (mmHg, 115±1 vs 133±2 respectively, P<0.05, n=5/group). Similar results were obtained with Ad-GFP-CYP4A10 shRNA compared to Ad-GFP Scr-shRNA transduced in the PVN on mean arterial pressure (MAP) measured by radiotelemetry (Day 12: mmHg, 121±4 vs 152±4 respectively, P<0.05, n=4/group) in CYP1B1 KO mice. The number of TMEM119
+
microglia and GFAP
+
astrocytes, markers of neuroinflammation determined by immunofluorescence, and ROS production by dihydroethidium staining followed the changes in blood pressure produced by Ang II in the above groups. To determine the contribution of central AA-CYP4A10-generated 20-HETE to Ang II-induced hypertension, the effect of 20-HETE receptor GPR75 siRNA administered intracerebroventricularly (Dharmacon, SMARTpool: 0.4 nmol 2
μ
l, single injection
)
was examined in CYP1B1KO mice. GPR75 siRNA but not its non-target siRNA minimized Ang II-induced increase in SBP (Day 12: mmHg, 132±4 vs 171±3, P<0.05, n=6/group). These data suggest that the 20-HETE receptor antagonist could be useful in treating hypertension and associated neuroinflammation in females with ovarian dysfunction.
Abstract P364: Chromatin Interactions Between Regulatory Elements Influence Gene Expression in Human iPSC-Derived Endothelial and Vascular Smooth Muscle Cells
Authors: Liu Pengyuan , Liu Yong , Pandey Rajan , Ray Atrayee , Huang Jing , Qiu Qiongzi , Greene Andrew , Cowley Allen , Geurts Aron , Rao Sridhar , Liang Mingyu
Published: October 2024

Most SNPs associated with blood pressure (BP) are located in noncoding regions of the human genome, where they may regulate gene expression in BP-relevant cell types. However, the mechanisms by which these SNPs influence BP regulation are unclear. To address this, we developed comprehensive epigenomic landscapes in human induced pluripotent stem cell (iPSC)-derived endothelial cells (iECs) and vascular smooth muscle cells (iVSMCs), incorporating DNA methylation analysis (RRBS), transcriptome analysis (RNA-seq), chromatin state profiling (ATAC-seq), and chromatin interaction mapping (Micro-C).

We identified 5301, 8916, and 6046 chromatin loops in iECs and 5329, 7598, and 5228 loops in iVSMCs at 4, 8, and 16 kb resolutions (FDR < 0.05) respectively based on the Micro-C analysis. Remarkably, 82.4% and 83.8% of these chromatin contact regions in iECs and iVSMCs, respectively, harbored at least one known regulatory element such as an enhancer, promoter, or transcription factor binding site. Notably, 109 and 119 BP-associated SNPs were found within the chromatin contact regions of iECs and iVSMCs, respectively.

We further investigated chromatin contact regions that involved interactions of regulatory elements. In both iECs and iVSMCs, lower methylation levels were observed in chromatin contact regions involving promoter-promoter (PP) and enhancer-promoter (EP) interactions, compared to enhancer-enhancer (EE), enhancer-transcription factor binding site (ET), and promoter-transcription factor binding site (PT) interactions. Additionally, greater chromatin accessibility was observed in chromatin contact regions involving PP and EP interactions. BP-associated SNPs were significantly enriched in chromatin contact regions involving PP and EP interactions. Moreover, genes proximal to chromatin contact regions involving PP or EP interactions exhibited higher expression than those near EE or other regulatory element interactions.

These findings offer new insights into how chromatin interactions between regulatory elements define transcriptional states in human endothelial and vascular smooth muscle cells, providing a novel basis for understanding the genetic regulation of BP.
Abstract P367: Cross-Species Epigenomic Maps of Intergenic Loci for Hypertension and Blood Pressure
Authors: Tutaj Monika , Lin Chien-Wei , Ray Atrayee , Yang Chun , Stelloh Cary , Liu Pengyuan , Liu Yong , Widlansky Michael , Greene Andrew , Geurts Aron , Cowley Allen , Liang Mingyu , Rao Sridhar , Kwitek Anne
Published: October 2024

Many non-coding SNPs identified in Genome-Wide Association Studies (GWAS) likely affect BP-related gene expression through epigenetic mechanisms. This study analyzes the comparative genomic and epigenomic landscapes in human and rat kidney tissues, including kidney proximal tubule (PT) and medullary thick ascending limb (mTAL), focusing on the major challenge of identifying conserved regulatory elements in intergenic regions. The purpose of our study is to identify BP gene regulatory elements in intergenic regions that are conserved from human to rat for
in vivo
validation and mechanistic studies. Our ultimate goal is to generate high-resolution, genome-wide epigenomic maps of key BP-relevant tissues, using ATAC-seq, Hi-C, CUT&Tag, DNA methylation profiling and RNA-seq.

We are creating visualization hubs for human and rat, integrating our data within the UCSC Genome Browser environment. UCSC contains extensive data for humans but very little for rats, particularly for the updated genome assemblies. To address this gap, we integrated our results with data from the Rat Genome Database (RGD). To date, we harmonized ATAC-seq data from human and rat PT and mTAL and displayed these data in RGD’s JBrowse2 genome browser for unique comparative genome views.

Based on our initial analysis of data density and intensity, we are developing a novel pattern recognition algorithm to identify epigenomic marks that are conserved across rat and human genomes. Existing algorithms predominantly focus on the conservation of coding genes, gene families, and genomic sequences. Here, average normalized peak intensities for ATAC-seq data across tissues were subject to canonical correlation between human and rat to identify conserved epigenomic patterns within the BP GWAS loci.

Here we present an example of a human BP locus in the intergenic region between
NPR3
and
TARS1
on chromosome 5 which has a region of conserved synteny with rat chromosome 2. Comparative analysis and visualization of this region show significant correlation between ATAC-seq peaks from rat and human PT and mTAL at this locus, with predicted conserved regulatory elements. These visualizations can uncover novel biological insights and identify potential regulatory targets for intervention. This work underscores the importance of advanced visualization techniques in understanding hypertension pathogenesis, facilitating cross-species comparisons, and enhancing the utility of genomic databases.
Abstract P372: Greater Long-Term Non-High Density Lipoprotein Cholesterol Variability From Childhood Is Associated With Higher Risk Of Early-Onset Hypertension: The Bogalusa Heart Study
Authors: Kang Soo Jung , Gill Eunsun , Hwang Phillip , De Anda-Duran Ileana , JIN XUANYI , Fernández Alonso Camilo , Bazzano Lydia
Published: October 2024

Background:
Early-onset hypertension is associated with greater risk of cardiovascular mortality and hypertension associated organ damage, compared to late-onset hypertension. Non-high-density lipoprotein cholesterol (non-HDL-C) is known to better predict future cardiovascular event risk, compared to low-density lipoprotein cholesterol. Whether higher long-term non-HDL-C variability from childhood is associated with higher risk of early-onset hypertension is unclear.

Methods:
We included 1271 participants of the Bogalusa Heart Study (age at enrollment: 9.9 ± 4.0 years, follow-up: 38.3 ± 3.8 years, age at last exam: 48.2 ± 5.2 years, 59.5 % women, 34.4 % Black participants) with ≥3 lipid measurements during follow-up. Non-HDL-C was calculated as total cholesterol (mg/dL) - HDL-C (mg/dL). Onset of hypertension was defined as having blood pressure ≥140/90 mmHg or using antihypertensive medications during follow-up. Participants were categorized according to age at hypertension onset (years) into 4 subgroups: <35 (early-onset), 35-44, ≥45, and people without hypertension. Long-term non-HDL-C variability was obtained from the deviation from age predicted values (DEV) and residual SD (RSD). DEV and RSD were calculated from growth curves derived from linear mixed effect models, as the mean and SD of the residuals of observed and predicted non-HDL-C levels. Associations between non-HDL-C variability and hypertension onset subgroups were analyzed using multinomial logistic regression models. Interactions by race and sex were performed.

Results:
For 1-SD increase in DEV and RSD of non-HDL-C, the odds of hypertension increased for all hypertension onset subgroups compared to people without hypertension, after adjusting for race, sex, diabetes, obesity, and smoking status, education, and non-HDL-C at last exam. The odds of hypertension was highest in the early-onset subgroup (Table). No significant interactions were found between both DEV and RSD and race and sex.

Conclusions:
Our findings suggest that individuals with higher long-term non-HDL-C variability may be at a greater risk of having early-onset hypertension.