bluuebunny/crossref_metadata_2025 huggingface dataset:
X-ray polarization signatures in bombarded magnetar atmospheres
Authors: Kelly Ruth M E , González-Caniulef Denis , Zane Silvia , Turolla Roberto , Taverna Roberto
Published: September 2024

Magnetars are neutron stars that host huge, complex magnetic fields which require supporting currents to flow along the closed field lines. This makes magnetar atmospheres different from those of passively cooling neutron stars because of the heat deposited by back-flowing charges impinging on the star surface layers. This particle bombardment is expected to imprint the spectral and, even more, the polarization properties of the emitted thermal radiation. We present solutions for the radiative transfer problem for bombarded plane-parallel atmospheres in the high magnetic field regime. The temperature profile is assumed a priori, and selected in such a way to reflect the varying rate of energy deposition in the slab (from the impinging currents and/or from the cooling crust). We find that thermal X-ray emission powered entirely by the energy released in the atmosphere by the magnetospheric back bombardment is linearly polarized and X-mode dominated, but its polarization degree is significantly reduced (down to 10 per cent–50 per cent) when compared with that expected from a standard atmosphere heated only from the cooling crust below. By increasing the fraction of heat flowing in from the crust the polarization degree of the emergent radiation increases, first at higher energies (${\sim} 10\ \mathrm{keV}$) and then in the entire soft X-ray band. We use our models inside a ray-tracing code to derive the expected emission properties as measured by a distant observer and compare our results with recent IXPE observations of magnetar sources.
Polyubiquitinated PCNA triggers SLX4-mediated break-induced replication in alternative lengthening of telomeres (ALT) cancer cells
Authors: Kim Sangin , Park Su Hyung , Kang Nalae , Ra Jae Sun , Myung Kyungjae , Lee Kyoo-young
Published: September 2024

Replication stresses are the major source of break-induced replication (BIR). Here, we show that in alternative lengthening of telomeres (ALT) cells, replication stress-induced polyubiquitinated proliferating cell nuclear antigen (PCNA) (polyUb-PCNA) triggers BIR at telomeres and the common fragile site (CFS). Consistently, depleting RAD18, a PCNA ubiquitinating enzyme, reduces the occurrence of ALT-associated promyelocytic leukemia (PML) bodies (APBs) and mitotic DNA synthesis at telomeres and CFS, both of which are mediated by BIR. In contrast, inhibiting ubiquitin-specific protease 1 (USP1), an Ub-PCNA deubiquitinating enzyme, results in an increase in the above phenotypes in a RAD18- and UBE2N (the PCNA polyubiquitinating enzyme)-dependent manner. Furthermore, deficiency of ATAD5, which facilitates USP1 activity and unloads PCNAs, augments recombination-associated phenotypes. Mechanistically, telomeric polyUb-PCNA accumulates SLX4, a nuclease scaffold, at telomeres through its ubiquitin-binding domain and increases telomere damage. Consistently, APB increase induced by Ub-PCNA depends on SLX4 and structure-specific endonucleases. Taken together, our results identified the polyUb-PCNA-SLX4 axis as a trigger for directing BIR.
DciA secures bidirectional replication initiation in Vibrio cholerae
Authors: Besombes Amelie , Adam Yazid , Possoz Christophe , Junier Ivan , Barre Francois-Xavier , Ferat Jean-Luc
Published: September 2024

Replication is initiated bidirectionally in the three domains of life by the assembly of two replication forks at an origin of replication. This is made possible by the recruitment of two replicative helicases to a nucleoprotein platform built at the origin of replication with the initiator protein. The reason why replication is initiated bidirectionally has never been experimentally addressed due to the lack of a suitable biological system. Using genetic and genomic approaches, we show that upon depletion of DciA, replication is no longer initiated bidirectionally at the origin of replication of Vibrio cholerae chromosome 1. We show that following unidirectional replication on the left replichore, nascent DNA strands at ori1 anneal to each other to form a double-stranded DNA end. While this DNA end can be efficiently resected in recB+ cells, only a few cells use it to trigger replication on the right replichore. In most DciA-depleted cells, chromosome 1 is degraded leading to cell death. Our results suggest that DciA is essential to ensuring bidirectional initiation of replication in bacteria, preventing a cascade of deleterious events following unidirectional replication initiation.
GeneSPIDER2: large scale GRN simulation and benchmarking with perturbed single-cell data
Authors: Garbulowski Mateusz , Hillerton Thomas , Morgan Daniel , Seçilmiş Deniz , Sonnhammer Lisbet , Tjärnberg Andreas , Nordling Torbjörn E M , Sonnhammer Erik L L
Published: September 2024

Single-cell data is increasingly used for gene regulatory network (GRN) inference, and benchmarks for this have been developed based on simulated data. However, existing single-cell simulators cannot model the effects of gene perturbations. A further challenge lies in generating large-scale GRNs that often struggle with computational and stability issues. We present GeneSPIDER2, an update of the GeneSPIDER MATLAB toolbox for GRN benchmarking, inference, and analysis. Several software modules have improved capabilities and performance, and new functionalities have been added. A major improvement is the ability to generate large GRNs with biologically realistic topological properties in terms of scale-free degree distribution and modularity. Another major addition is a simulation of single-cell data, which is becoming increasingly popular as input for GRN inference. Specifically, we introduced the unique feature to generate single-cell data based on genetic perturbations. Finally, the simulated single-cell data was compared to real single-cell Perturb-seq data from two cell lines, showing that the synthetic and real data exhibit similar properties.
Transformer model generated bacteriophage genomes are compositionally distinct from natural sequences
Authors: Ratcliff Jeremy
Published: September 2024

Novel applications of language models in genomics promise to have a large impact on the field. The megaDNA model is the first publicly available generative model for creating synthetic viral genomes. To evaluate megaDNA’s ability to recapitulate the nonrandom genome composition of viruses and assess whether synthetic genomes can be algorithmically detected, compositional metrics for 4969 natural bacteriophage genomes and 1002 de novo synthetic bacteriophage genomes were compared. Transformer-generated sequences had varied but realistic genome lengths, and 58% were classified as viral by geNomad. However, the sequences demonstrated consistent differences in various compositional metrics when compared to natural bacteriophage genomes by rank-sum tests and principal component analyses. A simple neural network trained to detect transformer-generated sequences on global compositional metrics alone displayed a median sensitivity of 93.0% and specificity of 97.9% (n = 12 independent models). Overall, these results demonstrate that megaDNA does not yet generate bacteriophage genomes with realistic compositional biases and that genome composition is a reliable method for detecting sequences generated by this model. While the results are specific to the megaDNA model, the evaluated framework described here could be applied to any generative model for genomic sequences.
Quantum geometry in condensed matter
Authors: Liu Tianyu , Qiang Xiao-Bin , Lu Hai-Zhou , Xie X C
Published: September 2024

One of the most celebrated accomplishments of modern physics is the description of fundamental principles of nature in the language of geometry. As the motion of celestial bodies is governed by the geometry of spacetime, the motion of electrons in condensed matter can be characterized by the geometry of the Hilbert space of their wave functions. Such quantum geometry, comprising Berry curvature and the quantum metric, can thus exert profound influences on various properties of materials. The dipoles of both Berry curvature and the quantum metric produce nonlinear transport. The quantum metric plays an important role in flat-band superconductors by enhancing the transition temperature. The uniformly distributed momentum-space quantum geometry stabilizes the fractional Chern insulators and results in the fractional quantum anomalous Hall effect. Here we review in detail quantum geometry in condensed matter, paying close attention to its effects on nonlinear transport, superconductivity and topological properties. Possible future research directions in this field are also envisaged.
Pulmonary and extra-pulmonary effects of lung transplantation in an Italian cohort of patients with systemic sclerosis
Authors: Iannone Claudia , Pellico Maria Rosa , Morlacchi Letizia Corinna , Rossetti Valeria , Vicenzi Marco , Beretta Lorenzo , Severino Adriana , Airò Paolo , Cacciapaglia Fabio , Codullo Veronica , Faggioli Paola , Iagnocco Annamaria , Meloni Federica , Mercante Lorena , Saracco Marta , Stano Stefano , Zaccara Eleonora , Minniti Antonina , Cavalli Silvia , Trignani Giorgia , Blasi Francesco , Nosotti Mario , Boffini Massimo , Caporali Roberto , Del Papa Nicoletta
Published: September 2024

Objectives

Lung transplantation (LuTx) is a life-saving intervention for SSc patients with end-stage lung disease. The aim of this study was to evaluate patients’ survival and LuTx outcomes on systemic disease manifestations.

Methods

A retrospective evaluation was conducted on SSc patients who underwent LuTx between 2010 and 2021. Outcomes assessed at baseline, 6, 12 and 24 months post-LuTx included skin involvement by modified Rodnan skin score (mRSS), and global disease activity using a modified EUSTAR index (0–9 scale). Lung function rescue was evaluated by forced vital capacity (FVC). Patient survival was assessed by Kaplan–Meier analysis.

Results

Thirteen SSc patients were included, with a male/female ratio 9/4 and a median age of 48.7 years. Nine patients were affected by diffuse cutaneous scleroderma (dcSSc) and four by limited cutaneous scleroderma (lcSSc). FVC significantly increased from 56% of the predicted value at baseline to 78% at 2 years (P = 0.003). mRSS decreased from 7.4 ± 3.8 to 3.3 ± 2.5 in patients with dcSSc (P = 0.02). The modified EUSTAR index score decreased from 2.54 ± 1.8 at baseline to 0.49 ± 0.5 at 2 years (P = 0.02). Survival rate was 92.3% at 2 years, and 76.9% at 5 years. No unexpected adverse events were observed.

Conclusions

In SSc patients undergoing LuTx, an excellent 2-year survival was observed, without any disease-related adverse events. Our study supports LuTx as a viable option in SSc patients with end-stage lung disease. Apart from expected recovery of lung function, LuTx was associated with improvement of mRSS and global systemic disease activity.
Melatonin facilitates oocyte growth in goats and mice through increased nutrient reserves and enhanced mitochondrial function
Authors: He Changjiu , Wu Hao , Liu Ruiyan , Liao Jianning , Wang Xiaodong , Shi Hongru , Hou Fuqin , Reiter Russel J. , Liu Guoshi , Li Xiang
Published: September 2024

Oogenesis involves two phases: initial volumetric growth driven by nutrient accumulation and subsequent nuclear maturation. While melatonin (MLT) has been employed as a supplement to enhance the quality of fully grown oocytes during nuclear maturation phase, its impact on oocyte growth remains poorly studied. Here, we provide in vivo evidence demonstrating that follicle‐stimulating hormone increases MLT content in ovary. Administration of MLT improves oocyte growth and quality in mice and goats by enhancing nutrient reserves and mitochondrial function. Conversely, MLT‐deficient mice have smaller oocytes and dysfunctional mitochondria. Exploring the clinical implications of MLT in promoting oocyte growth, we observe that a brief 2‐day MLT treatment enhances oocyte quality and reproductive performance in older mice. These findings highlight the role of MLT in regulating oocyte growth and provide a specific treatment window for optimizing oocyte quality and reproductive performance in female animals.
O02 SIMULTANEOUS BLOOD PRESSURE AND ATRIAL FIBRILLATION SCREENING IN MAY MEASUREMENT MONTH 2022
Authors: Beaney Thomas , Kerr Gabriele , Schlaich Markus , Schutte Aletta , Stergiou George , Poulter Neil , Freedman Ben
Published: September 2024

Background and objective:

May Measurement Month (MMM) is a global campaign aiming to raise awareness of raised blood pressure (BP). In 2022, concurrent screening for BP and atrial fibrillation (AF) was conducted in ten countries, given that hypertension and AF are both major treatable risk factors for stroke. Here, we evaluate AF prevalence and treatment by BP status among opportunistic samples of adults.

Methods:

In MMM, adults (≥18 years) undergo opportunistic BP screening. In ten participating countries, concurrent AF screening was carried out using OMRON Complete or M7 devices, in addition to three standardized, sitting BP measurements. ‘Known’ AF was defined as having had a previous diagnosis of either AF or irregular heartbeat, or taking oral anticoagulants. To risk-stratify those with AF, we calculated the CHA2DS2-VASc score. Hypertension was defined as a BP ≥140 and/or ≥90 mmHg (average of the second and third readings) and/or taking BP-lowering medication.

Results:

80,751 adults (mean age 50.1 years; 58.2% female) underwent BP and AF screening. AF was detected in 1,526 (1.9%), of whom 1,014 (66.4%) had ‘known’ AF. Of those with ‘known’ AF, 214 (21.1%) were taking anticoagulants and 644 (63.5%) were taking neither anticoagulants nor aspirin. AF was detected more commonly among those aged ≥60 than <60 (3.2% vs 1.2%: p<0.001). Hypertension was detected more commonly among those with than without AF (63.6% vs 45.2%; age-sex-adjusted p<0.001).

There was a graded association in anticoagulant and aspirin treatment rates according to CHA2DS2-VASc score in participants with ‘known’ AF (Table). Amongst participants with ‘known’ AF, anticoagulant usage was reported by 35.7% of those with a class 1 indication for anticoagulation according to CHA2DS2-VASc score.

Conclusions

Opportunistic AF screening in the MMM 2022 campaign detected AF in 3.2% of participants aged ≥60, and hypertension was more common in those with AF. Over one third of detected cases were not ‘known’ cases. Only 35.7% of ‘known’ cases with a class 1 indication for anticoagulants were treated.
O05 TERMINAL DIGIT PATTERN IN COMMUNITY-BASED HYPERTENSION SCREENING PROGRAMS: 5-YEAR ANALYSIS FROM MAY MEASURE MONTH NEPAL
Authors: Inagaki Yoko , Koirala Sweta , Mishra Shiva Raj , Adhikari Tara Ballav , Acharya Pawan , Kumar Payal Rajender , Devkota Surya , Khanal Pratik , McLachlan Craig , Neupane Dinesh
Published: September 2024

Background and Objectives:

Terminal digit preference leads to misclassification of hypertension. Despite strong promotion of community-based hypertension screening, the extent of terminal digit preference in such programs is not well understood. We aimed to identify the proportion of blood pressure (BP) ending in zero, and factors associated with the most repeated digit.

Methods:

A cross-sectional study was conducted using data from May Measure Month (MMM) Nepal 2017, 2018, 2020, 2021, and 2022. Participants with available data on the type of BP monitors were included. In MMM Nepal, adults≥18 years of age were eligible and recruited via convenience sampling. Data enumerators are community health workers or college students trained for BP measurement through short trainings. Without bias, the proportion of BP ending in zero is expected to be 10% and 20% for automated and manual monitors, respectively.

Results:

A total of 48,442 participant were included with 29.2% age≥50 years and 51.8% females. BP appeared to be normally distributed with “spikes” at terminal digits of zero (Figure 1). 90.9% of participants were measured their BP with automated monitors and 8.1% with manual monitors. The proportion of BP ending in zero was about 1.7 and 4.8 times greater than the expected proportion using automated and manual monitors, respectively (automated: 17.0% [SBP], 16.7% [DBP], manual: 95.3% [SBP], 93.8% [DBP]). Logistic regression showed age≥50 (OR 1.13 [95%CI 1.06, 1.20]) and SBP≥140mmHg (1.63 [1.49, 1.78]) were associated with SBP ending in zero, and age≥50 (1.14 [1.08, 1.22]) and DBP≥90 mmHg (2.11 [1.96, 2.28]) were associated with DBP ending in zero, both after controlling for sex, smoking, alcohol use, diabetes, cardiovascular diseases, antihypertensive medicine use, and the type of BP monitors used.

Conclusion:

The proportion of BP ending in zero was higher than expected with any type of BP monitors used. More studies are needed to investigate whether these distributions were by chance or due to errors.
O07 RENAL DENERVATION IMPROVES RIGHT VENTRICULAR FUNCTION, RESTORES MYOCARDIAL NOREPINEPHRINE LEVELS AND REVERSES VENTRICULAR SPECIFICITY OF SELECTED MARKERS IN HYPERTENSIVE RATS WITH HEART FAILURE INDUCED BY VOLUME OVERLOAD
Authors: Miklovic Matus , Gawrys Olga , Honetschlagerova Zuzana , Kala Petr , Huskova Zuzana , Kikerlova Sona , Vanourkova Zdenka , Adamova Marketa , Maxova Hana , Puertas-Frias Guillermo , Kvasilova Alena , Kitamoto Misuzu , Mracek Tomas , Sedmera David , Melenovsky Vojtech
Published: September 2024

Background and objective:

Despite the known anti-hypertensive effect of renal denervation (RDN), its influence on the cardiac function, particularly of the right ventricle (RV) and the cardiac sympathetic nervous system in heart failure (HF) is poorly understood. This study aimed to investigate the effect of RDN on RV function, myocardial norepinephrine (NE), and left versus right ventricular (LV/RV) dominance of HF markers in HF induced by aorto-caval fistula (ACF).

Methods:

ACF was created in hypertensive Ren-2 transgenic rats. RDN was performed by phenol application. Cardiac function was measured by echocardiography and pressure-volume analysis. NE levels were measured using an ELISA kit, protein expression was assessed by western blotting, gene expression by TaqMan PCR assay, and ROS by Amplex Red assay.

Results:

RDN in ACF rats decreased RV hypertrophy and dilatation, decreased RV end-systolic pressure and end-diastolic pressure, improved RV function (Ees +45%, FAC +20%), decreased HF gene markers Nppa, Tgm2, Myh7/6 ratio, and increased SOD2 protein expression. RDN decreased plasmatic NE levels, increased NE in RV, and decreased monoamine oxidase (MAO-A) in RV.

NE levels and SOD2 were more dominant in RV than LV in control (sham/intact) rats and ACF changed their specificity towards RV dominance, while RDN had no effect in these parameters in ACF on ventricular specificity.

In sham/intact rats dominant for LV were hemodynamic parameters Ees, EDPVR, and molecular markers Mao-a, ROS production by MAO-A, Nppa, Myh7, Myh7/6 ratio, Tgm2, Uchl1, and Beta1/Chrm2 ratio. ACF changed the dominance of these selected markers from LV to RV. Interestingly, RDN reversed dominance back towards LV in gene markers Mao-a, Nppa, Myh7, Tgm2, Uchl1, and Beta1/Chrm2 ratio.

Conclusions:

RDN decreased RV ESP and EDP, improved RV systolic function, restored NE levels, decreased RV gene expression of selected HF markers, and reversed their RV/LV dominance, probably by reduction of central sympathetic nerve drive and alternations of the cardiac sympathetic nervous system.
O08 TESTOSTERONE CAN INDUCE CARDIAC HYPERTROPHY IN OVARIECTOMIZED SPONTANEOUSLY HYPERTENSIVE RATS THROUGH THE ACTIVATION OF THE mTORC2/Atg9a
Authors: Wang Wenting , Yu Jing
Published: September 2024

Objectives:

The estrogen level of postmenopausal women decreased sharply, while the androgen level did not decrease significantly, which was characterized by the inversion of estrogen / androgen ratio. Therefore, it could be observed that relative excess androgen in the circulation of postmenopausal women, which may be one of the reasons for the increase of cardiovascular disease in postmenopausal women. In this study, the model of postmenopausal hypertension was established by bilateral ovariectomy in spontaneously hypertensive rats (SHR), and the specific mechanism of testosterone-induced myocardial hypertrophy in ovariectomized SHR was explored.

Methods:

24 SHR were randomly divided into four groups: WKY group (n=6), sham operation group (Sham group, n=6), bilateral ovariectomized group (OVX group, n=6) and testosterone propionate intervention group (OVX+T group, 6 mg/kg/Weekly, im for 4 weeks, n=6). Western Blot was used to detect the protein expression of β-MHC, ANP, Androgen receptor, Akt, p-Akt, mTORC2 and its subunits Rictor and LC3 and mitophagy related proteins.

Results:

1.The expression of β-MHC and ANP was significantly increased in the OVX and OVX+T groups when compared to the WKY and Sham groups. Additionally, the expression of androgen receptors was markedly upregulated in both the OVX and OVX+T groups. These findings strongly suggest that testosterone primarily induces myocardial hypertrophy in SHR after ovariectomy through androgen receptors.

2. Although no significant difference in mTORC2 expression was noted between the WKY, Sham, and OVX groups, testosterone exhibited a notable capacity to activate mTORC2 expression and the p-Rictor subunit in the OVX+T group.

3. The expression of LC3II/LC3I and DRP1 were increased in the OVX+T group when compared to the WKY, Sham and OVX groups. While the expression of MFN2 in the four groups shows no significant difference. Meanwhile, the expression of Atg9a was increased in OVX+T group.

Conclusions:

In bilateral ovariectomized SHR, testosterone has the potential to activate mitophagy by activating the mTORC2/Atg9a pathway, which, in turn, leads to cardiac hypertrophy.
O13 ASSOCIATION OF SECONDHAND SMOKE EXPOSURE IN RELATION TO HYPERTENSION TREATMENT STATUS WITH STROKE OCCURRENCE IN GHANA AND NIGERIA
Authors: Fakunle Adekunle , Asowata Osahon , Okekunle Akinkunmi , Sarfo Fred , Akpa Onoja , Wahab Kolawole , Akpalu Albert , Obiako Reginald , Akinyemi Rufus , Ovbiagele Bruce , Owolabi Mayowa
Published: September 2024

Background and objective:

It is unclear whether secondhand smoke exposure (SHSE) in hypertensive states with a disproportionate gap in hypertension treatment status is fuelling the epidemic of stroke in sub-Saharan Africa. This study, therefore, assessed the association of SHSE in relation to hypertension treatment status with stroke occurrence among West Africans.

Methods:

The Stroke Investigative Research and Educational Network (SIREN) is a case-control study across 16 study sites in Ghana and Nigeria. Cases were acute stroke (n =3684) with age- and sex-matched stroke-free controls (n =3684). Hypertension definition was based on standard guidelines, and SHSE was based on self-reported exposure to smoke from a burning cigarette or exhaled from a smoker in any indoor area. We evaluated the associations of untreated hypertension, treated but uncontrolled hypertension, and controlled hypertension at BP of <140/90 mmHg with odds of stroke occurrence. Multivariable-adjusted logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) of the risk of stroke by hypertension treatment and SHSE status.

Results:

Overall, mean age was 59.0±14.9 years, and 54.2% were male. Among stroke cases, the prevalence of SHSE was 352 (20.7%), and the frequencies of no hypertension, untreated hypertension, treated but uncontrolled hypertension, and controlled hypertension were 4.0%, 47.7%, 37.1%, and 9.2%. The aOR and PAR (95% CI) for untreated hypertension were 6.58 (5.15-8.41) and 35.4% (33.4-37.4); treated but uncontrolled hypertension was 9.95 (7.60-13.02) and 35.9% (34.2-37.5); and controlled hypertension was 5.37 (3.90-7.41) and 8.5% (7.6-9.5) respectively. The aOR (95% CI) of stroke, given exposure to secondhand smoke, was 1.15 (0.94-1.41), while among untreated hypertensives and treated but uncontrolled hypertensives was 1.54 (0.99-2.37) and 1.15 (0.48-1.46) respectively.

Conclusion:

SHSE with hypertension significantly aggravated the odds of stroke occurrence, particularly when hypertension is untreated. Implementing targeted multi-sectoral interventions that advocate for clean air and aggressive hypertension treatment can potentially reduce the escalating burden of stroke in Africa.
O14 KIDNEY RESIDENT MEMORY T CELLS MEDIATE THE CHRONIC PROGRESSION OF HYPERTENSION
Authors: Deck Katherine , Liu Yunmeng , Mora Christoph , Guo Yunping , Rafferty Tonya , Benson Lance , Mu Shengyu
Published: September 2024

A significant challenge in treating hypertension is insufficient blood pressure (BP) control and its recurrence. Previously, we described the contribution of CD8 T cells (CD8Ts) to the pathogenesis of salt-sensitive hypertension. Notably, despite antihypertensive therapy temporarily lowering BP in hypertensive mice, the T cell residency was not disrupted within the kidneys, and hypertension recurred when treatment was ceased. We hypothesize that the CD8Ts established a long-living resident memory (Trm) population in the kidney that instigates the recurrence of hypertension.

To examine this, we utilized both wild-type (WT) and T-cell-specific KO of TGFβRII (Tsp-TGFβRKO) mice, which prevents the formation of Trms. Blood pressure was recorded continuously with radiotelemetry. Hypertension was induced with the classic DOCA-salt model and an Angiotensin II (Ang II)-induced salt memory model to mimic the clinical recurrence of hypertension with high salt intake. In this salt-memory model, a one-week infusion of Ang II paired with high salt-induced hypertension before being allowed to return to normal blood pressure. A chronic high salt intake challenge then tested the recurrence of hypertension. Both splenic and renal T cell populations were characterized using flow cytometry.

As expected, DOCA-salt treatment led to salt-sensitive hypertension in WT mice along with the development of a significant CD8Trm population within their kidneys. These CD8Trms were notably diminished in the kidneys of DOCA-treated Tsp-TGFβRKO mice who also had attenuated blood pressure elevation. While testing the recurrence of hypertension during the Ang II-induced salt-memory model both WT and Tsp-TGFβKO reached the same degree of hypertension during Ang II-salt and baseline blood pressure before and after Ang II-salt. However, only the WT developed Trm and had the recurrence of hypertension with high salt challenge whereas both were lost in the Tsp-TGFβKO mice.

In summary, our study unveils the critical role of kidney CD8Trms in contributing to salt-sensitive hypertension and its recurrence. This leads to targeting key molecules that initiate the development of Trms to mitigate the persistency of hypertension.
O17 THE PROGRESSION OF HYPERTENSION WITH OBESITY AND DIABETES FAVORS CARDIAC PRO-INFLAMMATORY MACROPHAGES AND DIASTOLIC DYSFUNCTION
Authors: Sepúlveda R , Moya J , Rojas MSc J , Araos P , Amador C , Hermoso M , Gabrielli L , Jalil J , Ocaranza M
Published: September 2024

Background:

In most patients, hypertension (HT) is accompanied by obesity and diabetes. Cell-specific mechanisms like accumulation of macrophages, and dysregulation of innate immune pathways play important roles in cardiac remodeling (CR). Macrophages (Mo) exhibit phenotypic heterogeneity in response to tissue micro-environment. It is unknown whether in the heart the subpopulations of pro-inflammatory Mo (CCR2+MHCII+) and resident repair Mo (CCR2-MHCII+ and CCR2-MHCII-) differ in the development of the chronic HT, obesity and diabetes. Objective. To determine in male with HT and or obesity and diabetes, the pro-inflammatory cardiac Mo derived from monocytes (CCR2+MHCII+) and the resident repair Mo (CCR2-MHCII+ and CCR2- MHCII-).

Methods:

12-week-old male C57BL/6N mice were assigned to experimental groups: control diet, high-fat diet (HFD, 60% kcal from fat), L-NAME (L,0.65 g/L in drinking water) and HFD+L for 5 and 15 weeks. Body weight (BW), systolic (SBP) and diastolic blood pressure, glucose and exercise capacity (EC), cardiac function and cardiac Mo CCR2+MHCII+, CCR2-MHCII+, CCR2- MHCII- were determined.

Results:

(mean ± SEM, n=9-12). During 15 weeks, HFD and HFD+L groups showed significantly higher BW and glucose intolerance vs. control and L (p <0.001, F=28.4; p<0.001, F=10.3, respectively). EC as lower in the HFD and HFD+L groups compared to control and L (p<0.059). Echocardiographic parameters showed a significant increase in the size of the left atrium (p<0.001, F=38.9) and diastolic dysfunction in the HFD+L group vs control, HFD and L (p<0.001, F=35.6). No changes in ejection fraction and shortening fraction. The thickness of the septal wall and posterior wall was significantly greater in the HFD+L and HFD groups (p<0.0001, F=10.6 and p<0.0001, F=14.6, respectively). The L hearts showed a significant increase in CCR2-MHCII- (p<0.0001, F=68.6) and a significant decrease in CCR2+ MHCII+ (p<0.001, F=13.7), compared to the control and HFD groups.

Conclusion:

The progression of HT with obesity and diabetes favors cardiac pro-inflammatory macrophages and diastolic dysfunction.
O21 PLATELET COUNT-TO-PLATELET DISTRIBUTION WIDTH RATIO AND OTHER PLATELET INDICES AS COST-EFFECTIVE MARKERS OF PREECLAMPSIA: A CASE CONTROL STUDY
Authors: Bashyal Ritu , Sharma Paban Kumar , Singh Alka , Maharjan Sanjay , Tuladhar Shreyashi , Bhattarai Binita
Published: September 2024

Background and objective:

Platelet indices, like platelet count (PC), plateletcrit, mean platelet volume (MPV) and platelet distribution width (PDW), and their ratios have shown to be cost-effective and better predictors of preeclampsia (PE). However, PC/PDW ratio was not studied. Thus, this study aimed to compare platelet indices and their ratios between pregnant women with and without PE.

Methods:

An analytical, comparative, case-control study. Two groups were compared; pregnant women with PE (case, n=24) and without PE (control, n=72). The differences between cases and controls were compared using Student's t-test and Mann–Whitney U-test for continuous variables and chi-square tests and Fisher's exact test for categorical. Multivariable linear regression analysis for hematological parameters was performed to assess the effect of gestational age. Logistic regression was performed to calculate the odds ratio. Receiver operating characteristic curve was used to determine sensitivity, specificity and cutoff values. P < 0.05 was considered significant.

Results:

There was significant reduction in values of PC (p=0.004), plateletcrit (p=0.012), PC/MPV ratio (p=0.002), and PC/PDW (p= <0.001) among the pregnant women with PE compared to the control study group, while a significant increase was noticed in the values of PDW (p= <0.001) and MPV (p=0.021).

PC/PDW had the highest area under the curve (AUC) of 0.767, followed by PDW (AUC=0.752). At the cutoff value of 15.1 (p<0.001) for PC/PDW, sensitivity was 70.8%, and specificity was 81.9%. The odds of diagnosing true positive cases of PE was 11.02 (95% CI =3.79-31.99, p=<0.001) times higher compared to values below it at this cutoff point.

Conclusions:

Present study suggests that platelet indices are economical tests that can act as indicators of risk of PE. Among all the parameters, PC/PDW has the highest sensitivity and specificity in the detection of PE at the cutoff of 15.1 and has emerged as a better predictor of PE.
O26 SUSTAINED BLOOD PRESSURE CONTROL FOLLOWING A HOME BLOOD PRESSURE TELEMONITORING PROGRAM
Authors: Reynolds Kristi , Juan RA , Harrison TN , An J , Zhou H , Mefford MT , Marquez JM , Ong-Su AL , Brettler JW
Published: September 2024

Background and Objective:

Home blood pressure telemonitoring (HBPT) facilitates HBP monitoring and reduces office BP. Evidence whether BP control can be sustained via HBPT is lacking. We examined the effects of a HBPT program on sustained BP control.

Methods: We included patients enrolled in a HBPT program at a large integrated US healthcare system from November 2019-June 2022. Patients with uncontrolled hypertension were enrolled by a clinician, given a BP device and provided consent through an app. Patients were asked to measure their BP three mornings and three evenings each week before taking antihypertensive medication. BP readings were synced to the app, and non-physician providers titrated medications. Patients were successfully discharged from the program after achieving control (at least two 1-week average BPs and last BP in one month <135/85 mmHg). We examined mean clinic BP reduction before and after enrollment to HBPT and sustained BP control (last clinic BP <140/90 mmHg in the 12 months following discharge). Multivariable robust Poisson regression was used to identify factors associated with sustained BP control at 12 months.

Results:

A total of 3574 patients were enrolled and 2123 (59%) consented; of these, 63 (3%) did not submit >1 BP, 780 (37%) were actively enrolled, 644 (30%) disenrolled without meeting BP control and 636 (30%) achieved control and were discharged after a mean of 4 months. Among the 636 successfully discharged, 527 (83%) had clinic BP during follow-up. Compared with the last clinic BP prior to HBPT enrollment, mean (SD) clinic SBP and DBP was reduced by 16.3 (22.6) mmHg and 10.0 (12.3) mmHg, respectively (p<.0001 for both) and 75% of patients sustained BP control at 12 months. Younger patients and patients with high SBP prior to HBPT were less likely to sustain BP control at 12 months (Figure).

Conclusions:

While the HBPT program in this healthcare system shows promise for sustained BP control, strategies to enroll/consent patients and spread the program are warranted.
O27 DEVELOPMENT OF A CONCEPTUAL EVALUATION MODEL AND TESTING ITS PERFORMANCE IN HYPOTHETICAL PAY-FOR-PERFORMANCE INTERVENTIONS TO IMPROVE HYPERTENSION CONTROL
Authors: Marklund Matti , Rao Krishna D. , Cherukupalli Rajeev , Appel Lawrence J. , Matsushita Kunihiro
Published: September 2024

Background and Objective:

Hypertension is a growing concern, particularly in low- and middle-income countries. Financial incentives, such as pay-for-performance, have shown promise in improving non-hypertension outcomes. However, their efficacy and cost-effectiveness in hypertension management, especially in low-resource contexts, remain uncertain. Our objectives were to 1) document studies exploring health financial interventions for hypertension management 2) develop a conceptual model which can facilitate future research on health financing approaches for hypertension management, and 3) assess the model's performance in hypothetical pay-for-performance interventions.

Methods:

Our literature review identified few studies evaluating finance interventions on hypertension management with somewhat more evidence for pay-for-performance strategies. Thus, we developed a conceptual model and assessed its performance in hypothetical scenarios of pay-for-performance schemes to enhance public hypertension care in Bangladesh. Using a state-transition modeling framework, we estimated the incentive costs and impact on cardiovascular disease burden in 18 scenarios with varying intervention coverage, blood pressure effects, and incentive rates (Figure 1). Key model inputs were derived from the 2019 Global Burden of Disease Study, the 2018 WHO STEPS survey, and WHO-CHOICE. Our primary outcome was incentive costs per health-adjusted life year (HALY) gained.

Results:

Based on our model, the incentive costs per HALY gained depended on the intervention coverage, intervention effect and incentive rate (Figure). If only currently treated patients were included, the most optimistic scenario (i.e., the largest blood pressure reduction with the lowest incentive rate) was estimated to cost 11,043 USD in incentives per HALY gained (Figure). If the intervention also included new, previously untreated patients while maintaining the same total incentives, the estimated incentive costs per HALY gained was 5,515 USD.

Conclusions:

Our model suggests that pay-for-performance interventions for hypertension care may demand substantial financial resources, but that the intervention could become more favorable with increased treatment coverage. While more studies on the impact of financial interventions in hypertension care are necessary, our model can guide planning and designing such a study.
O64 ENHANCED EXPRESSION AND MEDIAL LAYER LOCALIZATION OF ELASTASE-2, AN ANGIOTENSIN ENZYME: IMPACT ON ABDOMINAL AORTIC ANEURYSM HALLMARKS IN MICE
Authors: Mestriner Fabiola , Dugaich Vinicius Flora , Dantas Pedro Bruch , Kovacs Henrique , Ribeiro Mauricio Serra , Becari Christiane
Published: September 2024

Abdominal aortic aneurysm (AAA) is a pathological dilation of the abdominal aorta that can lead to death, with no pharmacological treatment available other than repair surgery. Continuous angiotensinII (AngII) infusion induces AAA in mice. Elastase-2 (ELA-2), a chymotrypsin-serine protease and an elastase family member, acts as an AngII enzyme in arteries and contributes to resistance arteries and vascular remodeling in animal models. Therefore, ELA-2 is a potential factor in AAA formation and/or development. We sought to investigate the expression and localization of ELA-2 in AAA-induced mice.

Methods:

Male wild-type (C57bl/6,WT) and ELA-2knockout (CELA-2aTm1Bdr; ELA-2KO) mice treated with saline (WT+Sal n=10, ELA-2KO+Sal, n=9) or AngII (1.500ng/kg/min, WT+AngII n=8, ELA-2KO+AngII n=8) for twenty-eight days by subcutaneously mini-pumps infusion. Vascular ultrasonography (US, Vevo2100) analyzed, before and after treatment, aortic expansion index, aortic systolic and diastolic diameter parameters. The immunofluorescence for ELA-2, aorta layer, and histologic staining to collagen, elastin, and fibrosis was analyzed. A correlation between ELA-2 and US was done.

Results:

WT+AngII mice developed AAA, and ELA-2KO mice did not have AAA by infusion of Ang II. Aorta ELA-2 expression up-regulated in WT-AngII vs. WT+Sal (p=0.0001). Aortic systolic diameter increased in the WT+AngII vs WT+Sal (0.8vs.1.5 mm, p<0.0001). Aortic diastolic diameter increases in the WT+AngII vs WT+Sal (1.2 vs.0.6 mm, p<0.0001). The aortic expansion index decreases in WT+Ang II vs WT+Sal (11.4 vs.17.1%, p=0.0008). WT+AngII aorta has higher collagen deposition and fibrosis and lower elastin than WT+Saline (p=0.001). ELA-2KO+AngII vs. ELA-2KO+SAL showed no difference in elastin, collagen, and fibrosis. The analyzed parameters characteristic of AAA showed a positive correlation with ELA-2 in aorta middle layer in WT+AngII, where AAA develops.

Conclusion:

ELA-2 expression is up-regulated in AAA mice’s aorta and may contribute to developing aneurysms. ELA-2KO might be less susceptible to developing AAA induced by AngII infusion. Therefore, ELA-2 plays a significant role in AAA pathophysiology and could be a potential target for therapeutic treatment to prevent AAA development.
O37 LINK BETWEEN NMDA RECEPTOR GluN2C DEFICIENCY AND HYPERTENSION IN MICE
Authors: Jeon Sihyun , Romero Cesar
Published: September 2024

N-methyl-D-aspartate (NMDA) receptors are glutamate receptors located in the CNS and peripheral tissues. We previously demonstrated that kidney NMDA receptors in the connecting/collecting ducts (CNT/CCD) participate in renal autoregulation and kidney vasodilation. Additionally, we found that the use of non-specific NMDA inhibitors increases blood pressure. This study aims to identify which NMDA receptor subtypes are associated with hypertension. We evaluated the RNA transcription of the Grin2C gene (GluN2C subunit) and the Grin2D gene (GluN2D subunit) in the CNT/CCD using in-situ hybridization RNA scope, along with the presence of the CNT/CCD marker AQP-2. Blood pressure was evaluated in C57B mice and global genetic ablated mice on a C57B background: GluN2C-KO and GluN2D-KO. Blood pressure was measured using the tail-cuff method three times a week for two weeks following a three-session training period. Both male and female mice were used. Animals were fed regular and high salt diets (4%). RNA expression of NMDA subunits 2C and 2D was found in AQP2-positive regions of mouse kidneys, consistent with CNT/CCD regions. Females had higher Grin2C transcription levels than males (p<0.01). The average systolic blood pressure (SBP) for C57B control mice was 105.6±10.5 mmHg. SBP in GluN2C-KO mice was 114.6±7.3 mmHg, significantly elevated compared to the matched C57B control mice (p<0.01). SBP in GluN2D-KO mice was 111.6±10.4 mmHg, with no significant differences from the matched control (111.1±4.6 mmHg; p=0.93). GluN2C-KO female tends to have higher SBP tan males, however the difference was not statistical significant. Following a high salt diet challenge, blood pressure did not change in any of the three groups. NMDA receptor subunits GluN2C and GluN2D are expressed in the CNT/CCD region. The genetic absence of GluN2C is associated with increased blood pressure, whereas the lack of GluN2D did not affect SBP. No salt sensitivity was observed in any of the genetically ablated mice. Future research will explore the effects of these subunits on renal hemodynamics.
O39 IMPACT OF UROMODULIN CONCENTRATION ON RENAL AND HAEMODYNAMIC PARAMETERS IN A BLACK AFRICAN COMMUNITY WITH A HIGH PREVALENCE OF HYPERTENSION
Authors: Peterson Vernice , Charles Aaliah , Reddy Manishka , Gomes Monica , Du Toit Wessel , Woodiwiss Angela
Published: September 2024

Background and Objective:

The burden of hypertension (HTN) and related comorbidities disproportionately affects developing countries like South Africa, particularly in urban populations of African ancestry. This demographic exhibits a volume-dependent form of HTN that is resistant to antihypertensive drugs that target the renin-angiotensin-aldosterone system. Renal fluid retention or abnormalities may cause HTN in this group, thus the need to investigate various nephron components for a better understanding. Uromodulin is a potential biomarker for renal function and tubular reserve. However, the relationship with renal function, haemodynamic parameters and HTN in a Black African population is unknown. Therefore, the aim of this study was to explore the relationship between urinary uromodulin concentration and renal as well as haemodynamic parameters in a Black African community with a high prevalence of volume-dependent HTN.

Methods:

Systemic haemodynamics (central pressures [SphygmoCor] and echocardiographic aortic velocity and diameter measurements in the outflow tract), urinary uromodulin concentrations (ELISA assay) and renal function (creatinine clearance from 24-hour urine collections [n=370]) were determined in a Black African community (n=397).

Results:

No relationships between urinary uromodulin concentrations and age, body mass index, blood pressure or hypertension were noted. However, urinary uromodulin concentrations were higher in females than males, even after adjusting for several confounders (p=0.0007). Although urinary uromodulin concentrations were unrelated to renal function, an inverse relationship with stroke volume (SV) was observed (p=0.0023). The inverse relationship between SV and urinary uromodulin concentration was independent of confounders and present in hypertensives (p=0.007) but not normotensives (p=0.43). The hypertensives were noted to have a higher SV than the normotensives (p=0.047).

Conclusion:

In a Black African community sample with a high prevalence of volume-dependent primary hypertension, urinary uromodulin was inversely related to SV, particularly in participants with hypertension. These data suggest the need to investigate the mechanisms linking urinary uromodulin to haemodynamic parameters to identify novel pathways to target for better treatment strategies in hypertension.
O41 CLINICAL INERTIA IN PATIENTS WITH RESISTANT HYPERTENSION CONTROLLED BY AMBULATORY BLOOD PRESSURE MEASUREMENTS
Authors: Zanuzzi Matias , Bernabeu Francisco , Cornavaca Teresita , Romero Cesar
Published: September 2024

Background and objective:

Uncontrolled hypertension, especially among high cardiovascular risk patients like those with resistant hypertension (r-HTN), remains a significant public health concern. Clinical inertia, the failure to initiate or intensify therapy, is a major contributor to uncontrolled hypertension, including in r-HTN patients. We aimed to assess the prevalence of clinical inertia and its associated characteristics in r-HTN patients.

Methods:

A retrospective analysis of consecutive Ambulatory Blood Pressure Measurements (ABPM) in patients between August 2016 and August 2023 in a Cordoba, Argentina tertiary center was performed. r-HTN was defined by ABPM when optimal or best-tolerated doses of three drugs failed to control blood pressure (BP) or the patient received four or more drugs regardless of BP control. Therapeutic inertia was diagnosed when uncontrolled BP persisted without pharmacological changes in the subsequent visit to the ABPM. Failure to exclude secondary causes of hypertension constituted diagnostic inertia.

Results:

168 patients were included; mean age 66 years (Range 33-87), 55% females. r-HTN prevalence was 31.5% (53/168). Overall uncontrolled BP was 61.9% (104/168), with r-HTN patients exhibiting higher rates (75% vs 55.7%; p=0.014) of uncontrolled BP. Therapeutic inertia was 28.6% (48/168), being more frequent in r-HTN patients (41.5% vs 22.6%; p=0.012). Patients with therapeutic inertia had a greater number of comorbidities (1.2 ± 1.0 vs. 0.7 ± 1.0; p=0.003), diabetes (52% vs. 33%; p=0.024), more anti-hypertensive drugs (3.4 ± 0.6 vs. 3.2 ± 0.7; p=0.039), and higher BP values during ABPM. In a multiple regression model, only SBP24 independently predicted therapeutic inertia (p<0.01). Diagnostic inertia was 86.3% (145/168), lower in r-HTN patients (75.5% vs 91.3%; p=0.006). Patients with diagnostic inertia had lower BMI (30.0 ± 4.7 vs 31.2 ± 9.8; p=0.043), coronary artery disease (10% vs 26%; p=0.034), and fewer anti-HTN drugs (3.2 ± 0.6 vs 3.7 ± 0.9; p=0.002).

Conclusion:

Clinical inertia in resistant hypertension patients is highly prevalent, emphasizing the necessity of improving inertia to enhance blood pressure control and patient outcomes.

Table 2.- Clinical variables associated with the diagnosis of therapeutical inertia.
O47 THE ROLE OF IL-33 AND ST2 IN THE MODULATION OF TARGET ORGAN DAMAGE IN ANGIOTENSIN II-DEPENDENT HYPERTENSION
Authors: Saju Blessy , Nosalski Ryszard , Booth Emma , Guzik Tomasz
Published: September 2024

Introduction:

Hypertension is associated with a chronic inflammatory state and aberrant immune system activity. Interleukin-33/suppression of tumorigenicity 2 (IL-33/ST2) signalling axis is important in the modulation of atherosclerosis and cardiovascular fibrosis. We aimed to evaluate the modulation of IL-33 and ST2 in hypertensive mouse models and patients.

Methods and Results:

Hypertension was induced by a 14-day infusion of Ang-II (490ng/min/kg) in 12-week-old WT C57BL/6, ST2KO, IL33KO mice. IL-33 and ST2 mRNA and protein were evaluated using qPCR and Western blot in WT mice. Ang II-infusion significantly increased IL-33 and ST2 protein expression in target organs related to hypertension, particularly the aorta (1.0±0.1 vs 2.8±0.2, p<0.0001, and 0.963±0.068 vs 2.094±0.231, p=0.002, respectively). Further, mRNA expression of IL-33 and ST2 was elevated in hypertensive aortas when compared with control (1.0±0.053 vs 1.76±0.271, p=0.0185 and 1.0±0.039 vs 1.978±0.221, p=0.0039, respectively). IHC from WT mice illustrated the localisation of IL-33 and ST2 in Ang-II aortas in ECs and SMCs. Further in human hypertensive mammary arteries, the localisation was. In-vivo, IL33KO and ST2KO mice showed no altered BP at baseline or after 14 days of Ang-II compared to WT littermates. ST2KO Ang-II mice showed protection against endothelial dysfunction compared to WT Ang-II mice through isometric tension studies (p=0.0317). Additionally, Ang-II-induced IL33KO and ST2KO mice worsen cardiac fibrosis compared to WT littermates (p=0.0005,p<0.0001, respectively).

Conclusion:

Both IL-33 and its receptor, ST2 are increased in the vascular and perivascular tissues in hypertension. Additionally, the IL-33/ST2 axis has a role in regulating cardiac fibrosis.