bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 352: A Common Hypofunctional Genetic Variant of GPER: Increased Blood Pressure in Female Carriers and Increased Expression in Female Hypertensive Patients
Authors: Feldman Ross D , Gros Robert , Hegele Robert A , Ding Qingming , Hussain Yasin , Ban Matthew R , McIntyre Adam D 
Published: July 2021

Activation of the aldosterone/estrogen GPCR, GPER, has been linked to vasodepressor effects. Further, genetic deletion of GPER in one mouse model has been linked to increased blood pressure in female but not male mice. However, the significance of GPER regulation for chronic blood pressure control in humans is unknown. To examine this question we determined the functional significance of expression of a common missense single nucleotide variant of GPER, P16L, and the impact of its expression on blood pressure and in the development of hypertension.
Expression of the GPER P16L variant in rat aortic vascular smooth muscle cells vs. expression of wild type (WT) GPER, was associated with a significant decrease in G1 (1μM, a GPER agonist)-mediated ERK activation and G1-mediated inhibition of apoptosis.
In normotensive subjects, expression of this hypofunctional GPER variant (allele frequency=22%) paralleled an increase in mean arterial blood pressure in females [P16/P16: 80±1 mmHg (n=236) vs P16L carriers: 82±1 mmHg (n=156), p<0.05] but not in males.
To validate the importance of expression of the GPER P16L variant on the development of hypertension, we compared the allele frequency in normotensive vs. hypertensive subjects, the latter recruited from patients referred to a tertiary care level hypertension clinic (n=151). In this hypertensive patient population, the P16L allele frequency was increased in female patients with hypertension (1.4 fold, p<0.05 vs. allele frequency in normotensives) but was not increased in hypertensive males.
In summary, we have determined that the common genetic variant, P16L GPER, is hypofunctional and that expression of this missense single nucleotide polymorphism is associated with increased blood pressure in normotensive subjects and with an increased frequency in hypertensive female but not male patients.
Cumulatively, these data suggest that in females, impaired GPER function is associated with increased blood pressure and risk of hypertension.
Abstract 379: Circulating T Regulatory Lymphocytes and Microvascular Structural Alterations in Hypertensive Patients and Normotensive Subjects
Authors: De Ciuceis Carolina , Rossini Claudia , Airò Paolo , Scarsi Mirko , Tincani Angela , Solaini Leonardo , Agabiti Rosei Claudia , La Boria Elisa , Sarkar Annamaria , Porteri Enzo , Gavazzi Alice , Petroboni Beatrice , Rizzoni Damiano , Agabiti Rosei Enrico 
Published: July 2021

Background and Methods.
Different components of the immune system, including innate immunity and adaptive immunity (T effector lymphocytes and T regulatory lymphocytes: Tregs) may be involved in the development of hypertension. In addition, it was recently demonstrated that Tregs may prevent angiotensin II-induced vascular injury/inflammation, while Th1, Th2 and Th17 may play a role in the progression of vascular remodeling. However, no data are available in human beings about relationships between T-lymphocyte subtypes and microvascular structure.

In the present, preliminary study, we enrolled 7 normotensive subjects and 3 hypertensive patients undergoing an election surgical intervention. No sign of local or systemic inflammation was present in any subjects or patients. All patients underwent a biopsy of subcutaneous fat during surgery. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, morphological parameter were measured, in particular media to lumen ratio (M/L) was calculated. A peripheral blood sample was obtained before surgery for assessment of T lymphocytes subpopulations by flow cytometry.
Results are summarized in the Table. RTE: recent thymus emigrant; naïve: no contact with antigens, TDEM: highly antigen-experienced cells that assume pro-apoptotic properties. Additional significant positive correlations were observed between M/L and Th17 effector lymphocytes: r=0.67, p<0.05).

Conclusion
Our data suggest that some lymphocytes subpopulations may be related to microvascular remodeling, and open the possibility to regress small artery remodeling in human by specific drug modulation of lymphocyte subtypes.
Abstract 603: Effective And Sustained ACE2 Delivery Using Minicircles Technology
Authors: Wysocki Jan , Haber Philipp K , Ye Minghao , Maier Christoph , Osborn Mark J , Batlle Daniel 
Published: July 2021

Chronic and sustained amplification of ACE2 activity
in vivo
has required the development of

transgenic mice or the use of viral vectors. Minicircle is a new gene delivery technology
which is resistant to gene silencing, and therefore represents an attractive

platform for gene replacement strategies
in vivo
. Here we cloned cDNA of

soluble mouse ACE2 into a circular expression cassette and the resulting ACE2

minicircle (MC) was injected to female
FVB

mice using iv. hydrodynamic approach (10ug or 30ug/mouse). At 3-7d after MC
administration, serum ACE2 activity in mice that received 10ug ACE2MC (n=9) was
over 100-fold higher than in controls (n=9) (138±48 vs 0.7±0.2 RFU/uL/hr) and in
ACE2MC mice (30ug) (n=8) was almost 1000-fold higher than in controls (n=14) (480
±153 vs 0.5±0.1 RFU/uL/hr, respectively). Mice that received 10 ug ACE2MC were
followed for consecutive serum ACE2 activity monitoring, BP measurements and
plasma Ang levels. The increase in serum ACE2 activity was sustained until the
end of the study (up to 82 days) (Figure).
Despite such a marked increase in serum ACE2 activity in ACE2MC mice, conscious
SBP was not different from controls (137±8 vs 138±7 mmHg, respectively). At the
end of the study, when Ang II was infused acutely (0.2 ug/kg BW i.p.), the
increase in plasma Ang II in ACE2MC mice was significantly reduced compared to
control mice (915±154 vs 1420±131 fmoL/mL, p<0.05).
Mini-circle delivery of ACE2 results in a dose-dependent and sustained long-term
increase in serum ACE2 that efficiently degrades plasma Ang II. Extremely high
increases in serum ACE2 activity do not reduce BP probably due to activation of
non-ACE2 dependent compensatory Ang-hydrolyzing pathways.
Abstract 608: Circulating Soluble Insulin Receptor Level Is Associated With Left Ventricular Hypertrophy And Cardiac-dysfunction Independent Of Blood Pressure And Glucose
Authors: Takata Yasunori , Funada Junichi , Hiasa Go , Matsumoto Yuji , Sato Sumiko , Yoshii Toyofumi , Okayama Hideki , Kawamura Ryoichi , Onuma Hiroshi , Osawa Haruhiko 
Published: July 2021

Recent studies have demonstrated that both insulin resistance (IR) and diabetes were the critical risk factors of heart failure (HF). Importantly, it is reported the high prevalence of previously unknown left ventricular dysfunction including the prevalence of HF preserved EF (HFPEF) in diabetic subjects. However, the underlying mechanism and a biomarker have not been well defined.
To identify underlying mechanism and candidate biomarker of HF in subjects with type 2 diabetes (T2DM), we performed retrospective study of 143 T2DM and 181 non-diabetic subjects. We evaluated cardiac function by echocardiography measuring left ventricular ejection fraction (LVEF), left ventricular mass index (LVMi) and the ratio of early transmitral flow velocity to tissue doppler early diastolic mitral annular velocity (E/e’).

Here we demonstrate that plasma soluble insulin receptor (sIR), a novel biomarker of diabetes, was associated with left ventricular hypertrophy (LVH) and cardiac-dysfunction. Simple regression analysis revealed that circulating sIR was positively correlated with fasting glucose and negatively correlated with fasting insulin. Furthermore, sIR was positively correlated with LVMi and E/e’, and inversely correlated with LVEF (
R
=0.25;
p
<0.01,
R
=0.22,
p
=0.03,
R
=-0.19;
p
=0.02, respectively). Moreover, multivariable regression analysis revealed that sIR was associated with LVMi, E/e’ and LVEF after adjustment for age, gender, BMI, plasma fasting glucose, systolic blood pressure, and eGFR in subjects with T2DM (
β
= 0.26;
p
<0.01,
β
=0.25;
p
=0.02,
β
=-0.23;
p
<0.01,respectively). It is reported that circulating sIR is associated with cleavage of the extracellular domain of insulin receptor and sIR binds to circulating insulin. Thus, our results suggest the possibility that the influence of sIR on insulin signaling may be involved in LVH and cardiac-dysfunction in subjects with T2DM.
Abstract 265: Validation of a novel Brachial Pulse Wave Analysis-Based Method for Estimating Central Blood Pressure among Japanese Cardiovascular Patients
Authors: Shoji Toshihiro , Okada Sho , Nakagomi Atsushi , Kobayashi Yoshio 
Published: July 2021

Background:
Hypertension is a significant predictive factor for future cardiovascular(CV) events. Historically its assessment has been made at the brachial arm, and this method is still cardinal for hypertension treatment.

Blood pressure measured at the root of the aorta, named ‘central’ blood pressure (cBP), shows actual load on the heart and proximal large arteries. It has been recognized as more accurate predictor for CV events than ‘brachial’ one. Despite this, invasive maneuvers on cBP measurement have long limited its widespread clinical use.
Recently several non-invasive methods were developed for cBP measurement. ARC Solver algorithm, which calculates cBP from brachial BP using novel pulse wave analysis-based method, enabled us to assess ambulatory cBP values. Though it was already validated among western countries, its accuracy nor optimal conditions still remains unknown among us Japanese.

Object:
To validate ARC Solver algorithm-based cBP measurement among Japanese CV patients.

Method:
For 89 patients who underwent elective coronary angiography in our hospital, we simultaneously measured invasive cBP (cBPinv) and calculated cBP with ARC Solver algorithm (cBPcalc) . We used systolic and diastolic BP (Calc1) or mean and diastolic BP(Calc2) for calibration. Then we evaluated the error and correlation of the data with Bland-Altman analysis and Pearson correlation analysis, respectively. After excluding the perturbing factors such as arrhythmia and valvular heart disease, we performed the same analyses.

Results:
cBPinv and cBPcalc showed good linear correlation (Cal1: r=0.72, p<0.01, Cal2: r=0.748, p<0.01), whereas error between them showed marked difference (Cal1: 17.7±16.3mmHg, Cal2: -7.5mmHg±18.1mmHg).

After excluding perturbing factors, the difference even enlarged (Cal1: 19.9±17.0mmHg, Cal2: -3.9±15.5mmHg), although linear correlation was each improved (Cal1: r=0.76, p<0.05, Cal2: r=0.84, p<0.01). Gender difference influenced the error.

Conclusions:
Mode of calibration significantly influences the calculated cBP with ARC Solver algorithm among Japanese patients with CV diseases. Consideration for the perturbing clinical factors and gender difference are also essential for its proper clinical application.
Abstract 271: Developmental Origin Of Obesity Related Hypertension: Trans-generational Cardiovascular Impact Of High Fat Diet Feeding In Rabbits
Authors: Lim Kyungjoon , Burke Sandra L , Davern Pamela J , Head Geoffery A 
Published: July 2021

We determined if exposed to a high fat diet (HFD) during development have a similar phenotype (changes in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA)) in the offspring as adult obesity when consuming a HFD.
New Zealand White breeder rabbits were placed on a normal or 13.5% high fat diet (HFD) from 3 weeks prior to mating, during pregnancy and during lactation. Maternal NFD (mNFD) offspring was divided to two groups and placed on HFD for 10 days (mNFD+10dHFD) to mimic adulthood obesity. Rabbit offspring were implanted with renal electrode to measure RSNA. At 18 weeks of age, rabbits were infused with alpha-melanocyte-stimulating hormone (αMSH, 10nmol), Leptin antagonist (100μg), SHU9119 (melanocortin 3 and 4 receptor antagonist, 0.0375nmol, 0.075nmol, 0.1875nmol and 0.375nmol) and vehicle intracerebroventricularly.
There was no difference in baseline BP between all diet groups but baseline RSNA was increased in mHFD offspring (17.6 normalised unit (nu)) and mNFD+10dHFD offspring (10.7 nu) when compared to mNFD offspring (5.6 nu). αMSH injection increased BP (from 68 to 75mmHG, p<0.01) in mNFD+10dHFD offspring and HR was increased (from 159bpm to 246bpm, p<0.01) in maternal HFD offspring. When SHU9119 was injected, there was a reduction in BP in both maternal HFD (from 71 to 65mmHG, p<0.001) and mNFD+10dHFD (from 78 to 72mmHG, p<0.01) offspring. Leptin antagonist had no effect on BP in all diet groups but RSNA was reduced (29% reduction from 13 normalised unit) in mHFD offspring.
The phenotype of developmental obesity shows similar characteristics of adulthood obesity where the elevation of RSNA induced by HFD is predominantly mediated by increased sensitivity of the leptin signalling pathway.
Abstract 442: Cardiomyocyte Specific mTORC1 Deletion Precipitates Interstitial Fibrosis, Heart Failure And Loss Of Female Cardio Protection
Authors: Guergen Dennis , Kusch Angelika , Kauz Nelli , Catar Rusan A , Brink Marijke , Dragun Duska 
Published: July 2021

Mechanistic target of rapamycin (mTOR) kinase operates in two functionally and structurally distinct multiprotein complexes mTORC1 and mTORC2. mTORC1 including its defining raptor protein is a critical mediator of myocardial growth. We induced cardiomyocyte specific raptor-KO (cKO) deletion to investigate a sex specific role of mTORC1 during cardiac adaptation in normotensive DOCA-salt mice. Untypical for this mild cardiac stress model, raptor-cKO females had sharper decrease in EF (51 vs. 26%) than males (50 vs. 32%) already at 3 weeks after start of DOCA-salt challenge. Male raptor-cKO mice mounted eccentric hypertrophic response upon DOCA-salt indicated by heart weight/tibia length ratios (6.7 to 8.0) as compared to their WT litters (6.6 to 7.6). In contrast female raptor-cKO (5.8 to 6.4) minimally differed from their litters (5.8 to 6.6). Severe dilative phenotype was detected in both sexes regardless of DOCA-salt challenge. In addition, we found tremendous diffuse left ventricular fibrosis which was also more prominent in raptor-cKO females. Collagen depositions in the LV visualized by Sirius red staining increased 10fold in males (1.0 to 10.6%) and 15fold in females (0.9 to 15.7%), respectively. Expression of raptor protein in the heart was diminished by 80% in raptor cKO mice of both sexes what lead to similar extent of decreased activity of direct mTORC1 downstream targets phospho-S6 ribosomal protein and phospho-4E-BP1Ser65 (68% reduction in males vs. 61% in females. Over-compensatory mTORC2 activation in cKO animals via phospho-AKTSer473 (12fold increase) and induction of anti-apoptotic signaling was similar in both sexes. However, raptor-cKO females failed to up-regulate expression of mitochondrial genes such as Mtnd1 (ND1), mt-Co1 (COX1) and Atp5i (ATP5k), stressing sex differences in mTORC1 dependent mitochondrial adaptation. In addition, transmission electron microscopy (TEM) points towards structural alterations of mitochondrial morphology.
Intact mTORC1 function is important for myocardial adaptation in both sexes. More severe phenotype in females further implicates mTORC1 to be essential for intrinsic female cardio protection.
Abstract 576: Relaxin Dit Not Improve Outcome In An Established Preeclamptic Transgenic Rodent Rat Model
Authors: Haase Nadine , Golic Michaela , Herse Florian , Przybyl Lukasz , Müller Dominik N , Dechend Ralf 
Published: July 2021

Preeclampsia affects 5% of pregnancies in industrialized nations and consists of hypertension and proteinuria and characterized by maternal endothelial dysfunction and excessive vascular inflammation starting after 20 weeks of gestation. It represents a major cause for fetal and maternal morbidity and mortality and is an established risk factor for subsequent cardiovascular disease.
Relaxin is a peptide hormone secreted by the corpus luteum, circulating in maternal blood during pregnancy. Its administration leads to rapid and sustained vasodilation. We hypothesized that relaxin ameliorates symptoms of preeclampsia in an established rat model. We used rats transgenic for the human angiotensinogen (hAogen) gene and the human rennin (hRen) gene and crossed the strains to produce a model of preeclampsia in the dams. On gestational day 9, hAogen TGR dams (PE rat) were randomly assigned to 2 experimental groups: vehicle (20 mM sodium acetate, pH 5.0,) or relaxin, at a dose of 2 μg/h of relaxin by subcutaneous osmotic minipump (Alzet, Typ 2002) until day 21 of gestation. Mean blood pressure was continuously recorded by radiotelemetry and 24 hour urine samples were collected in metabolic cages at day 18 of gestation. Rats were killed at day 21 of gestation. The fetuses and organs were removed and weighed.
Vehicle treated PE rats developed hypertension abruptly at gestational day 13 and had sustained hypertension. Relaxin treatment did not prevent the increase in blood pressure in the last third of pregnancy (MAP on day 16 of gestation: 151.1 ± 2.2 mmHg vehicle vs. 156.6 ± 1.3 mmHg relaxin). Proteinuria was not ameliorated by relaxin (14.6 ± 5.5 mg/d vehicle vs. 20.8 ± 3.8 mg/d relaxin treated group). The number of live fetuses was similar between the groups. In addition, reduced fetal and uteroplacental unit weights were unaffected by relaxin treatment. Furthermore, relaxin treatment had no influence on intra uterine growth restriction, measured by brain to liver ratio (0.795 ± 0.021 vehicle vs. 0.795 ± 0.016 relaxin). Our data demonstrate that relaxin did not ameliorate hypertension, proteinuria or IUGR in a transgenic rat model for preeclampsia.
Abstract P018: Periodic Water Intake Exacerbates Hypertension, Decreases Renal Function and Increases Renal Inflammation in Spontaneously Hypertensive Rats
Authors: Hilliard Lucinda M , Bulmer Louise , Mirabito Katrina M , Vinh Antony , Denton Kate M 
Published: July 2021

Water is essential for life. The kidneys are major regulators of fluid balance but also appear susceptible to adverse effects of periodic water intake since epidemiological studies have linked low water intake to chronic kidney disease. However, the impact of periodic water intake on renal health has largely been ignored. This study investigated the chronic effects of periodic drinking on blood pressure, kidney function, and immune cell infiltration in rats with pre-existing hypertension.
Mean arterial pressure (MAP) was measured continuously in spontaneously hypertensive rats (SHR) that were only given access to water for 2 hours per day versus control rats given free access to water over a 4-week period (n=>8 per group). Glomerular filtration rate (GFR) was measured via transcutaneous FITC-sinistrin clearance at baseline and at the end of the 4-week protocol. Renal immune cell infiltration and cytokine production was assessed by flow cytometry.
Basal MAP and renal function were similar between the control and water-restricted (WR) groups. Water restriction led to a significant increase in MAP from baseline (8.8±4.5mmHg versus 0.6±5.5mmHg in WR and control SHR, respectively; P<0.05). Moreover, GFR decreased from baseline by 29±6% in the WR SHR (P<0.001). In comparison, GFR did not change significantly over time in the control SHR (-5.3±2.6% from baseline; P>0.05). The increase in MAP and reduction in renal function in the WR-SHR was associated with periodic increases in urine osmolality (69±26% versus baseline, P<0.05), indicative of cycles of dehydration and replenishment. Renal immune cell infiltration was similar between the groups. However, cytokine analyses revealed a phenotypic shift towards a pro-inflammatory Th1 phenotype in kidney T cell infiltrate from WR versus control SHR. This was indicated by a greater proportion of T cells producing IFN-γ in SHR subjected to water restriction than control SHR (9.5±3.3% versus 2.9±0.9%, respectively; P<0.05).
In conclusion, recurrent dehydration associated with periodic drinking exacerbates hypertension, renal dysfunction and inflammation in male SHR. This highlights the importance of regular water intake for the maintenance of kidney health, particularly in populations with existing disease.
Abstract P052: Homocysteine Increases Macrophage-Derived Paraoxonase -1 Expression Independent of CD68
Authors: Chernyavskiy Ilya , Winchester Lee , Veeranki Sudhakar , Tyagi Suresh 
Published: July 2021

Although atherosclerotic plaque rupture is the leading cause of myocardial infarction, the mechanisms are unclear. Macrophages burdened with oxidized LDL (oxLDL) become foam cells: hallmarks of plaque progression and instability. One of the main macrophage-specific receptors for oxLDL is CD68. Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated lactonase capable of retarding/inhibiting LDL oxidation. Elevated levels of homocysteine (Hcy), an amino acid homologue and independent cardiovascular risk factor, is metabolized by Pon1.
Given the literature connections of oxLDL, Pon1, Hcy, and macrophages to atherosclerosis, we hypothesized that Pon1 is produced by murine macrophages and its expression is increased by Hcy via CD68.
Murine J774a.1 macrophages were treated with LDL, oxLDL, Hcy, or oxLDL+Hcy. Also, separate treatment groups included macrophages that had CD68 silenced by CD68 siRNA transfection. Cell lysates were analyzed for CD68 and Pon1 expression via Western blotting.
Pon1 is present in macrophages. Hcy along with oxLDL significantly increases Pon1 (51%, 1.51 vs 0.97) expression compared to controls than oxLDL alone. Pon1 expression is significantly decreased (33%, 0.67 vs 1) with silencing of CD68. Pon1 expression is significantly decreased more with oxLDL (82% 0.17 vs 1) in presence of CD68 silencing but is significantly increased with oxLDL+Hcy (24% 1.24 vs 1). CD68 expression tends to increase more with oxLDL+Hcy than oxLDL alone when compared to control and the tendency follows with silencing of CD68. Our results conclude that Hcy increases macrophage-derived Pon1 expression independent of CD68.
Abstract P147: Office Blood Pressure: An Inadequate Guide to the Diagnosis and Treatment of Hypertension
Authors: Cohn Jay , Duval Sue , Florea Natalia , Hoke Lynn , Duprez Daniel 
Published: July 2021

Hypertension is a cardiovascular (CV) disease with high risk for CV morbid events (ME) that benefits from anti-hypertensive therapy. Resting blood pressure (BP) >140/90 mmHg serves as the diagnostic criterion for hypertension, and management has been aimed at BP reduction. Progression of CV disease in the absence of elevated blood pressure identifies individuals who might benefit from CV-protective therapy but are not currently being recognized as in need of treatment.
In 2017 asymptomatic individuals evaluated for early functional and structural CV abnormalities, 1534 not taking anti-hypertensive drugs were available to determine the relationship between office blood pressure and the severity of CV abnormalities, as defined by a 10-test non-invasive disease score (DS) of 0-20. Previous studies have documented the high predictive value of DS for future CVME.
The population was 53% male, average age 50±11 years, BP 122/77mmHg, LDL cholesterol 129±38 mg/dL, HDL 52±17mg/dL, triglycerides 109 mg/dL. DS was adjusted by eliminating the score for BP, but 9-test DS was still directly related to BP: 2.3 in those (n=550) <120/80 mmHg (Group I), 3.2 in those 120-129/80-85 mmHg (n=600) (Group II), 4.1 in those 130-139/85-89 mmHg (n=236) (Group III), and 5.7 in those 140+/90+mmHg (n=148) (Group IV). Nonetheless, DS of >6 indicative of high risk was present in 10% of Group I, 20% of Group II and 30% of Group III. BP was largely overlapping in individuals with no CV disease (DS 0-2), early disease (DS 3-5) and advanced disease (DS 6+).
Therefore, reliance on resting BP leaves many at-risk individuals undiagnosed and untreated for early CV disease likely to progress. The hypertensive state exists in the absence of elevated BP and should be recognized and treated to prevent CVME.