bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P425: Ras Blockade Alone or Combined With Inhibition of Soluble Epoxide Hydrolase: Effects on the Course of Congestive Heart Failure in Ren-2 Transgenic Hypertensive Rats With Aorto-caval Fistula
Authors: Kala Petr , Sedlakova Lenka , Vanourkova Zdenka , Kopkan Libor , Sadowski Janusz , Kompanowska-Jezierska Elzbieta , Hwang Sung H , Hammock Bruce , Cervenka Ludek
Published: July 2021

Rationale and Objective:
We recently showed that increasing epoxyeicosatrienoic acids (EETs) in kidney by blocking soluble epoxide hydrolase (sEH), an enzyme responsible for EETs degradation, markedly attenuated the development of renal dysfunction and progression of aorto-caval (ACF)-induced congestive heart failure (CHF) in Ren-2 transgenic hypertensive rats (TGR). Therefore, in this study we examined if additional inhibition of sEH to RAS blockade could further improve the course of ACF-induced CHF in TGR.

Methods:
The treatment regimens were started from one week after creation of ACF and the follow-up period was 60 weeks. RAS blockade was achieved by administration of angiotensin-converting enzyme inhibitor (ACEi, trandolapril, 3 mg/L in drinking water) and sEH was blocked using a sEH inhibitor (sEHi,
c
-AUCB, 3 mg/L in drinking water). The following experimental groups were investigated: 1) Sham-operated TGR; 2) Untreated ACF TGR; 3) ACF TGR + ACEi; 4) ACF TGR + ACEi + sEHi (n = 36 in each ACF group). In separate groups renal hemodynamics and excretory function were evaluated two weeks post-ACF, just before the onset the decompensated phase of CHF.

Results:
After 29 weeks post-ACF, no animal survived. ACEi treatment greatly improved the survival rate (87%) at the end of study. Surprisingly, combined treatment with ACEi and sEHi worsened the rate (53%,
p
< 0.05). After 2 weeks post-ACF, untreated TGR group showed lower mean arterial pressure (MAP) (124 ± 3 vs. 146 ± 4 mmHg,
p
< 0.05), renal blood flow (7.6 ± 0.3 vs. 10.5 ± 0.3 mL.min
-1
.g
-1
,
p
< 0.05) and absolute sodium excretion (0.18 ± 0.06 vs. 1.09 ± 0.19 μmol.min
-1
.g
-1
, p<0.05) than sham-operated TGR group, respectively. The treatment with ACEi alone or combination treatment with sEHi did not prevent the changes in renal hemodynamics and sodium excretion.

Conclusion:
We found that addition of sEHi to ACEi treatment did not provide better protection against CHF progression and the survival rate, indeed, decreased significantly. Thus, increasing bioavailability of tissue EETs in individuals with pharmacologically-induced suppression of the RAS is not a promising approach to further attenuate renal dysfunction and progression of CHF.
Abstract P431: Renal Artery Stenosis Caused by a Bcr-Abl Tyrosine Kinase Inhibitor: Blood Pressure Response to Revascularization
Authors: Hiremath Swapnil , Amin Syed O , Ruzicka Marcel , Burns Kevin
Published: July 2021

Introduction:
Bcr-Abl tyrosine kinase inhibitors (TKI) are first line agents for management of chronic myelogenous leukemia (CML). Amongst the second generation TKIs, which have less resistance and improved side effect profile, nilotinib and ponatinib have also been reported to be associated with vascular adverse events (VAEs), including systemic and peripheral arterial stenosis. We report on a patient with CML treated with ponatinib, who developed bilateral renal artery stenoses, difficult to control hypertension, and responded to revascularization.

Case:
A 55 year old man, with CML due to a Bcr-Abl truncating mutation diagnosed in 2007, was treated with ponatinib 45 mg daily starting in 2011, which induced a complete remission. He subsequently developed hypertension. Hypertension appeared angiotensin II-dependent as BP normalized on combination of candesartan 32 mg once daily and hydrochlorothiazide 25 mg once daily. This treatment was however associated with an increase in serum creatinine from 1.4 to 2.6 mg/dL. Consistent with our clinical suspicion, a computed tomography angiogram revealed bilateral renal artery stenosis. He eventually required bilateral renal artery angioplasty and stenting as the BP could not be controlled without renin-angiotensin system blockers despite using up 5 classes of BP lowering drugs. Furthermore, follow up imaging of renal arteries showed progressive renal artery stenosis bilaterally. He underwent angioplasty and stenting in the left renal artery and angioplasty of both the branches of the right main renal artery, which could not be stented because of the early branching. After 6 months, BP is within target with 8 mg candesartan, amlodipine 10 mg and bisoprolol 2.5 mg daily, and the renal function is stable (creatinine 1.1 mg/dL). Overall, in this case, renal artery angioplasty and stenting stabilized renal function and improved control of hypertension.

Discussion:
Second generation TKIs are associated with VAEs, including renal artery stenosis. Renal artery angioplasty and stenting stabilized renal function and improved control of hypertension in this case. Future research should clarify the mechanisms of VAEs with TKIs, natural history, and long term response to revascularization in this setting.
Abstract P444: Surveillance, Control, and Prevention Systems and Community Engagement Process of Hypertension in Singburi, Thailand
Authors: Tiienthavorn Vichai
Published: July 2021

Background:
Recently,the patients of non-communicable diseases are increasing in Thailand; especially hypertension. However,finding high blood pressure early, treating and keeping it in the normal range can reduce the risk of developing complications such as Stemi and Stroke. Thailand has 10 million hypertension patients in 2013. Hence, Thai Government has policy to reduce the NCDs such as hypertension.

Methods:
This study was to convert disease oriented to health promotion approach to primary health care, using “ VICHAI’s 7 Color Balls Model”, which was used for primary screening of hypertension. The target population aged 15-65 which covering more than 90% of Singburi population. The screening result was classified by types and levels of severity of hypertension (blood pressure).The 7 colors are referred to normal <120/80 mmHg, white, risk 120/80-139/89 mmHg, light green, risk medication <139/89 mmHg, dark green, mild 140/90-159/99 mmHg, yellow, moderate 160/100-179/109 mmHg, orange , severe >180/110 mmHg, red, and patients with complication (black). The normal and risk group measured BP every 3 months, while the patient group did every month.

Results:
The control and prevention systems were developed to follow up patients using investigation, health education to encourage strictly medication and their behavioral change with best practice of 3Es(Eating,Exercise,Emotion) and 3Rs (Reducing tobacco,alcohol, obesity). Screening Hypertension was coverage 97.41% (2014-2015),normal group (white) increased from 72.55% to 74.94%, Significantly severe patients (red) were decreased to moderate (orange) from 0.11% to 0.07% and the complicated patient with STEMI decreased of 17.14% Furthermore, treatment cost decreased 3.9 million baht.

Conclusions:
This project is expanding in all provinces of Thailand as it is now one of the priority government policy. And it is the first demonstration of knowledge transfer to community engagement by student, which is the sustainable education in primary health care.

Main Message:
Finally, outcome of this study not only reduce the patient and mortality rate but also increase the quality of life, could apply in different areas and propose to be the national policy, effectively for a long term operation.
Abstract P448: Interaction Between Ischemic Brain Injury and Amyloid-β Deposition in Cognitive Decline; Possible Cognitive Protection by AT
2
Receptor Activation
Authors: Min Li-Juan , Mogi Masaki , Tsukuda Kana , Bai Hui-Yu , Shan Bao-Shuai , Higaki Akinori , Iwanami Jun , Horiuchi Masatsugu
Published: July 2021

Objectives:
Cerebrovascular damage could breakdown amyloid-β (Aβ) clearance and accelerate Aβ deposition. We examined the interaction between ischemic brain damage and Aβ deposition in cognitive function, focusing on the roles of angiotensin II type 2 (AT
2
) receptor in vascular smooth muscle cells (VSMC).

Methods:
Male wild-type mice (WT) or the mice with VSMC-specific AT
2
receptor overexpression (smAT
2
) were used. Mice were subjected to ICV injection of Aβ1-40. Ischemic brain injury was induced by bilateral common carotid artery occlusion (BCCAO) 24 hours after Aβ1-40 injection. Three weeks after Aβ1-40 injection, cognitive function was evaluated by the Morris water maze test. Brain samples obtained 8 days after Aβ1-40 injection were used to study the related signals.

Results:
ICV injection of Aβ1-40 in WT showed impaired cognitive function (arriving time to platform at day 5: control, 26.53±4.46 sec; Aβ, 65.35±7.44 sec), whereas BCCAO alone did not decline significantly cognitive function. In contrast, BCCAO following Aβ1-40 injection exhibited more marked cognitive impairment (84.27±8.00 sec) compared to Aβ injection alone with the increase in expressions of NADPH oxidase subunits such as p22phox and p67phox in the hippocampus of mice. Aβ1-40 injection with BCCAO tended to increase the mRNA levels of inflammatory cytokines such as MCP-1 and TNFα. BCCAO significantly enhanced the expression of Aβ clearance factor, RAGE (receptor for advanced glycation end product). Aβ1-40 injection did not increase the neuron pyknosis in the hippocampus, whereas the number of neuron pyknosis was increased significantly with BCCAO (control, 6.33±0.88/field; Aβ with BCCAO, 46.33±4.10/field). On the other hand, smAT
2
did not show cognitive impairment, the changes of the expression for NADPH oxidase subunits and inflammatory cytokines, and neuron pyknosis, which were induced by BCCAO with/without Aβ1-40 injection in WT.

Conclusion:
Ischemic brain injury could enhance Aβ-induced cognitive impairment with possible involvement of enhanced oxidative stress, neuron degeneration, and breakdown of RAGE-mediated Aβ clearance. AT
2
receptor activation in VSMC could play inhibitory roles in the cognitive decline induced by ischemic brain damage and Aβ deposition.
Abstract P455: Obesity Types (Body Mass Index vs. Waist Circumference) Affect on Development of Major Cardiovascular Risks: Data From Korean National Health Insurance Service - National Sample Cohort (NHIS-NSC)
Authors: Cho Eun Joo , Park Sungha , Lee Hae Young , Sung Ki Chul , Pyun Wook Bum , Shin Jinho , Cho Myeong-Chan
Published: July 2021

Background:
Population based study demonstrated that obesity (defined as increased body mass index, BMI) is important predictor for developing hypertension and diabetes mellitus (DM), which have been well known major cardiovascular (CV) risk factors. Increased waist circumference (WC) representative of central obesity is focused as main factor for developing CV disease and its major risks. This study was to evaluate obesity as a predictor for new onset of hypertension and DM within 1-year in previously normotensives or normoglycemic subjects.

Methods:
The Korean National Health Insurance Service - National Sample Cohort (NHIS-NSC) established data about BMI and WC with medical, social and familial histories in 2009 and have been followed up for 1 years. Among total 349257 subjects with age more than 20 year-old, 95124 (normotensive group: 75.2% of population were 25-55 year-old, 54121(56.9%) male) of normotensives for evaluate new hypertension and 120501 (normoglycemic group: 83.6% of population were 25-65 year-old, 67183 (55.8%) male) normoglycemic subjects for evaluate new DM were analyzed.

Results:
During 1-year follow-up period, 3773 (3.97%) new hypertension in normotensive group and 1594 (1.32%) new DM in normoglycemic group were developed. Binary logistic regression analysis revealed that BMI was the predictor (Exp(B)=1.18, Sig<0.001) for new onset hypertension with age (Exp(B)=1.31, Sig<0.001), sex (Exp(B)=0.664, Sig<0.001), dyslipidemia and family history of hypertension. For new onset DM, WC (Exp(B)=1.04, Sig<0.001), age (Exp(B)=1.26, Sig<0.001), sex Exp(B)=0.664, Sig<0.001) and family history of DM (Exp(B)=1.76, Sig<0.001) were the independent predictors.

Conclusion:
Increase of BMI is independent predictor for new onset hypertension and increase of WC is independent predictor for new onset DM within 1-year. Obesity type might affects development of different major CV risks and hence, obesity itself is the important risk factor for CV disease.
Abstract P456: Examining Framingham Coronary Heart Disease 10-year Risk Reduction in Individuals Treated With Lorcaserin, a Selective 5HT
2C
Receptor Agonist for Weight Management
Authors: Knoth Russell , Li Xuan , Chatterjee Debanjana , Fujioka Ken
Published: July 2021

Introduction:
Obesity contributes significantly to cardiovascular disease (CVD) risk and weight management is associated with CVD risk reduction. Lorcaserin, a selective 5HT
2C
receptor agonist, is indicated as an adjunct to a reduced-calorie diet and increase physical activity for weight management in adults with obesity (BMI≥30) and overweight (BMI 27-29.9 and ≥1 weight-related comorbidity). This analysis used the Framingham 10-year CVD risk to examine the impact of lorcaserin treatment on CVD risk and risk reduction.

Method:
Pooled data from two randomized, double-blind studies (BLOOM & BLOSSOM) investigating the efficacy of lorcaserin vs. placebo among non-diabetic patients with overweight or obesity, were used in this analysis. Framingham CVD risk was calculated for those whose lipid values were available at baseline and at one year. A Framingham CVD risk of <5% was classified as low risk. Patients were stratified by cohort, lorcaserin (LOR) vs. placebo (PBO) and response at week 12 (≥5% weight loss vs. < 5%) for calculating the 10-year CVD risk at one year. Logistic regression was used to adjust for baseline risk and determine if proportional differences in risk reduction were significant.

Results:
A total of 5,658 patients were evaluated, 51% treated with LOR. Among the LOR-treated patients, 43% achieved ≥5% weight loss at week 12 (compared to 19% treated with PBO). At one year, more patients in the LOR cohort had reduced CVD risk (from high to low risk, 21% vs. 15%, respectively). The regression analysis showed LOR-treated patients were 34% more likely to have low CVD risk (p<0.001). Similarly, for patients who lost ≥5% baseline body weight at 12 weeks, more patients in the LOR cohort had reduced CVD risk (from high to low risk, 26% vs. 16% respectively) at one year. The regression showed LOR-treated patients were 23% more likely to have low CVD risk (p<0.05).

Conclusion:
The analysis suggests that patients treated with LOR are more likely to have low CVD risk at one year than those treated with PBO. The effect is magnified if patients have ≥5% weight loss at 12 weeks.
Abstract P457: Hypertensive, Type II Diabetic and Obese Patients, Are Better Controlled and Reduce the Number of Drugs When Empagliflozin is Added to Standard Treatment Improving Also Arterial Stiffness and Central Blood Pressures
Authors: Cabrera-Sole Ricardo , Turpin Lucas Caridad , Urrera Rivera Liliana , Garcia Ruiz Santiago , Aguilera Manuel
Published: July 2021

Introduction:
It is known the difficulty of adequate control of blood pressure (BP) with a single drug, being necessary in most use 2 or more antihypertensive drugs. If they are also obese and diabetic, require even more drugs so we present our experience of adding empagliflozin to the treatment of patients with these characteristics.

Objectives:
To assess the benefits of metabolic ,BP and arterial stiffness parameters introducing empagliflozin in obese ,hypertensive and diabetics patients (PHTAD).

Material and Methods:
we studied 32 PHTAD receiving at least 3 drugs (ACE inhibitors, calcium channel blockers, hydrochlorothiazide) and two or more anti diabetic drugs (metformin, glimepirina, sitagliptin, insulin and Statins) for controlling their pathologies). We checked number of drug, BP, glicosylated hemoglobin (A1cHb), BMI and arterial stiffness measured by augmentation index (AI) and pulse wave velocity (PWV) and central systolic blood pressure (SBPc). Patients were followed for 32 weeks, adding to the beginning of the study empagliflozina .Every two months we checked them . The beginning and the end results were compared and are set out in the following table.

*means p value less than 0.05

Conclusions:
According to our data, the introduction of empagliflozin to the treatment of PHTAD significantly improves metabolic parameters and helps to reduce the number of antihypertensive and antidiabetic drugs they are taking, improving the arterial stiffness indexes and the central pressure values, obtaining a clear improvement in the control of their cardiovascular risk . So it should be thought about this group of drugs when it comes to medicating PHTAD.
Abstract P468: Stimulation of Diuresis and Salt Excretion by Renomedullary Infusion of a Dual Inhibitor of Fatty Acid Amide Hydrolase (FAAH) and Monoacylglycerol Lipase (MAGL)
Authors: Ritter Joseph K , Ahmad Ashfaq , Daneva Zdravka , Dempsey Sara , Li Guangbi , Li Ningjun , Lichtman Aron , Poklis Justin , Li Pin-Lan
Published: July 2021

The endocannabinoid, anandamide (N-arachidonoyl ethanolamide, AEA), is proposed to have a critical role in blood pressure regulation in the renal medulla. Infusion of AEA into the renal medulla of anesthetized C57BL6/J mice stimulated diuresis and sodium and potassium excretion without affecting blood pressure or glomerular filtration. AEA may act by direct stimulation of its cognate receptors or by either its hydrolysis and conversion to prostaglandins or a cyclooxygenase-2 (COX-2) dependent metabolite. The finding that intramedullary infusion of isopropyl dodecyl fluorophosphate (IDFP) produced the same profile of effects as AEA suggests that the hydrolysis of AEA to release arachidonic acid is not necessary for its efficacy and supports that endogenous endocannabinoids contribute to control of basal tone of renal excretory function. Blockade of the urine formation- and salt excretion- stimulating effects of intramedullary AEA and IDFP by a COX-2 (celecoxib) but not COX-1 (SC-560) inhibitor is consistent with elevated AEA in the renal medulla enhancing formation for a COX-2 metabolite of AEA that mediates the observed increases in diuresis and salt excretion. The effect of IDFP on urine formation rate was blocked in FAAH
-/-
mice, but unexpectedly IDFP intramedullary infusion lowered mean arterial pressure in FAAH KO mice, which may be explained by release into the blood of another endocannabinoid metabolized by MAGL or other serine hydrolase. It is concluded that the diuretic effect of intramedullary IDFP is mediated by inhibition of FAAH leading to elevation of endogenous AEA and a COX-2 dependent metabolite of AEA.
Abstract P494: Long-term Outcomes of a Cluster-randomized Trial Testing the Effects Blood Pressure Telemonitoring and Pharmacist Management
Authors: Margolis Karen L , Asche Stephen E , Bergdall Anna R , Dehmer Steven P , Green Beverly B , Sperl-Hillen JoAnn M , O’Connor Patrick J , Nyboer Rachel A , Pawloski Pamala A , Maciosek Michael V , Trower Nicole K
Published: July 2021

Background/Aims:
Hypertension is a common condition and leading cause of cardiovascular disease. We previously reported results of a cluster-randomized trial evaluating a home blood pressure (BP) telemonitoring and pharmacist management intervention, with significant reductions in BP favoring the intervention arm over 18 months. This analysis examined the durability of the intervention effect on BP through 54 months of follow-up and compared BP measurements performed in the research clinic and in routine clinical care.

Methods:
The Hyperlink trial randomized 16 primary care clinics having 450 study-enrolled patients with uncontrolled hypertension to either Telemonitoring Intervention (TI) or usual care (UC) study arms. BP was measured as the mean of 3 measurements obtained at each research clinic visit. General linear mixed models utilizing a direct likelihood-based ignorable approach for missing data were used to examine change from baseline to 54 months in systolic and diastolic BP (SBP and DBP).

Results:
Research clinic BP measurements were obtained from 326 (72%) study patients at the 54 month follow-up visit. Routine clinical care BP measurements were obtained from 444 (99%) of study patients from 7025 visits during the follow-up period. For TI patients, based on research clinic measurements baseline SBP was 148.2 mm Hg and 54 month follow-up was 131.2 mm Hg (-17.0 mm Hg, p<.001). For UC patients, baseline SBP was 147.7 mm Hg and 54 month follow-up was 131.7 mm Hg ( -16.0 mm Hg, p<.001). The differential reduction by study arm in SBP from baseline to 54 months was -1.0 mm Hg (95% CI: -5.4 to 3.4, p=0.63). For TI patients, baseline DBP was 84.4 mm Hg and 54 month follow-up was 77.8 (-6.6 mm Hg, p<.001). For UC patients, baseline DBP was 85.1 mm Hg and 54 month follow-up was 79.1 mm Hg (-6.0 mm Hg, p<.001). The differential reduction by study arm in DBP from baseline to 54 months was -0.6 mm Hg (95% CI: -3.5 to 2.4, p=0.67). SBP and DBP results from routine clinical measurements closely approximated the pattern of results from research clinic measurements.

Conclusion:
Significant BP reductions in the TI arm relative to UC were no longer seen at 54 month follow-up. To maintain intervention benefits over a longer period of time additional intervention is needed.
Abstract P501: Editing of Myosin Phosphatase Gene as a Novel Approach for Vasodilator Sensitization and Lowering of Blood Pressure
Authors: Meddeb Mariam , Ursitti Jeanine , Reho John , Fisher Steven A
Published: July 2021

Myosin Phosphatase (MP) is the primary effector of vascular smooth muscle (VSM) relaxation and a key end target of signaling pathways that regulate vessel tone. Regulated splicing of alternative Exon24 (E24) of Myosin Phosphatase Regulatory/ Targeting subunit (MYPT1) sets vasodilator sensitivity. Skipping E24 codes for a Mypt1 isoform that contains a C-terminal leucine zipper (LZ) motif required for cGK1α binding and NO/cGMP activation of MP resulting in vasodilation. Inclusion of 31 nt E24 shifts the reading frame coding for a Mypt1 isoform with a distinct C-terminus (LZ-) that is unresponsive to NO/cGMP. We are using two editing approaches to test the function of Mypt1 E24 splice variants in the control of BP in vivo. First, LoxP sites were inserted in introns flanking E24, crossed with smMHCCre
ER
, and treated with Tamoxifen to achieve smooth muscle-specific cKO of E24 (SMcKO E24), thereby converting Mypt1 to the LZ+ isoform. E24 cKO mice had mean BP that was 15
+
3 mmHg lower than control (n=3-5; p<0.05). Mesenteric arteries from these mice were significantly more sensitive to DEA/NO mediated relaxation (EC
50
: 2.1+0.5 nM vs 18.2+5.6 μM; n=5-6, p<0.05). We now are developing CRISPR/CAS9 editing of Mypt1 for translation into humans with hypertension. Guide(g)RNAs targeting E24 were designed using Benchling.com and selected for further study based on predicted efficacy, specificity (>10%,>60%) and cross-species conservation. Plasmids were generated by sub-cloning of oligonucleotides into the parent pX601 plasmid for the purpose of co-expression of gRNA and saCas9. These plasmids were transfected into HEK293 cells singly and in combinations and Mypt1 gene editing assayed by PCR, Surveyor nuclease assays and sequencing of genomic DNA. Single gRNAs yielded deletions of 1-3 nt. Combinations yielded deletions of 104-334 nt that removed >80% of E24 with an efficiency of editing that varied from 10% (gRNAs 6+9 and 5+9) to 40% (gRNAs 6+11 and 5+11). We have now generated AAVgE24 and are testing their efficiency of editing of VSM in vivo. These studies support that AAV mediated CRISPR/Cas9 editing of Mypt1 E24 could be a novel strategy for vasodilator sensitization and effective lowering of blood pressure in humans.
Abstract P511: Targeting Il-1β Protects From Aortic Aneurysms Induced by Disrupted Tgfβ Signaling in Smooth Muscle Cells
Authors: Carnevale Daniela , Carnevale Raimondo , Da Ros Francesco , Iacobucci Roberta , Casaburo Manuel , Cifelli Giuseppe , Carnevale Lorenzo , Perrotta Marialuisa , Bressan Giorgio , Lembo Giuseppe
Published: July 2021

Aortic aneurysms represent a life-threatening condition because of the current lack of effective treatments. Aneurysm formation is typically associated with extracellular matrix remodeling and persistent inflammation. Although the molecular mechanisms underlying aortic pathology remain largely unclear, TGFβ signaling is unquestionably implied and its downstream target Smad4 showed protective functions for maintenance of aortic walls’ integrity. Using mice with smooth muscle cells (SMCs) specific deletion of
Smad4
in the adult (
Smad4
-SMC
iko
), developing spontaneous aneurysms (Ascending Aorta Diameter:
Smad4
-SMC
iko
2.15±0.03;
Smad4
-SMC
wt
1.7±0.03;***p< 0.001), we investigated the molecular mechanisms activated by dysregulation of TGFβ signaling. Structural disarrangement of ascending aorta in
Smad4
-SMC
iko
mice was clearly appreciated early after Smad4 deletion as discrete breaks of elastic lamellae (breaks/section:
Smad4
-SMC
iko
2.05±0.5;
Smad4
-SMC
wt
0.83±0.4;***p< 0.001). Interestingly, the islands of damage in the aorta of
Smad4
-SMC
iko
were enriched of immune infiltrate, mainly monocytes/macrophages, as indicated by FACS and immunofluorescence. We then analyzed several pathways downstream to Smad4 inhibition, finding a selective activation of NF-kB/IL-1β in SMCs. To test the relevance of this pathway in the formation of aneurysms, we deleted
Smad4
in SMCs of mice with
Il1r1 null
background (
Smad4
-SMC
iko
;
Il1r1
-/-
). Ultrasonographic analyses revealed that ablation of IL1 receptor1 protected
Smad4
-SMC
iko
mice from the progression of pathology and improved their overall survival. In the end, to test the translational potential of our findings, we neutralized IL-1β signaling with the clinically relevant murine version of the FDA-approved clinical drug canakinumab. During a time course of 16 weeks, while a weekly administration of control immunoglobulins did not change aneurysm progression in
Smad4
-SMC
iko
mice, treatment with anti-IL-1β antibody significantly hampered aneurysm formation in the aorta (
Smad4
-SMC
iko
+anti- IL-1β 1.85±0.02;
Smad4
-SMC
iko
+anti-IgG 2.09±0.03; ***p< 0.001) These findings identify a mechanistic target for controlling aneurysms progression induced by disrupted TGFβ signaling.
Abstract P514: Age-related Differences in the Annual Changes of the Ankle-brachial Pressure Index: Underlying Mechanisms
Authors: Fujii Shogen , Shiina Kazuki , Chikamori Taishiro , yamashina Akira , Matsumoto Chisa , Komatsu Shunsuke , Tomiyama Hirofumi
Published: July 2021

Objectives:
The present prospective observational study was conducted to examine the age-related annual changes of the ankle-brachial pressure index (ABI) and their association with the longitudinal changes of the brachial-ankle pulse wave velocity (baPWV), a marker of arterial stiffness, and the radial augmentation index (rAI), a marker of the pressure wave reflection in middle-aged Japanese men.

Methods and Results:
In 4264 men (42 ± 9 years old) of a Japanese construction company, the ABI, baPWV and rAI were measured annually over a 9-year observation period. During the study period, ABI (from 1.10 ± 0.07 to 1.13 ± 0.07), baPWV (from 1295 ± 194 to 1344 ± 217 cm/sec) and rAI (from 69 ± 13 to 72 ± 13 %) were increased significantly (p<0.01). Mixed model linear regression analysis of the repeated-measures data revealed that the annual increase of the ABI was lower in men aged over 50 years of age (n = 1237: 0.28 ± 0.06) than in those aged under 50 years of age (n = 3027: 0.50 ± 0.04) (p < 0.01). Furthermore, while increased baPWV (estimate = 0.017, p < 0.05) and increased rAI (estimate 0.254, p < 0.05) were significantly related to the annual increase of the ABI in men aged <50 years (p < 0.01), no such association was observed in men aged
>
50 years.

Conclusion:
In middle-aged Japanese men, the ABI increases with age until the age of 50 years, and increased arterial stiffness and increased pressure wave reflection may contribute to this annual increase. In men aged
>
50 years, the annual increase of the ABI was attenuated, which could be related, at least in part, to the attenuation of the increase of the pressure wave reflection and also attenuation of the effect of increased arterial stiffness on the hydrostatic pressure in the arteries with age. These findings may suggest the usefulness of ABI measurement as a screening tool for peripheral arterial disease in men over 50 years old.
Abstract P524: Vasoprotective Effect of Hesperidin in the Onset of Arterial Hypertension Induced by L-NAME
Authors: Priviero Fernanda , Tomazini Goncalves Tiago , Martins Lazaro Carolina , Mezencio Jackeline , Araujo Natiele , Claudino Mario A , Carvalho Patricia , Webb R Clinton
Published: July 2021

Hesperidin has been used to manage venous disease and has been shown to have vasodilator, antiinflammatory and antioxidant properties. The aim of this work was to evaluate the efects of acute treatment with hesperidin (HD) on the vascular reactivity of rats in the onset of arterial hypertension induced by L-NAME. Male Wistar rats were divided into 3 groups as follow: 1- Control (CTL); 2- L-NAME (LN); 3- L-NAME + Hesperidin (LNHD). LN was given by gavage at the dose of 75mg/Kg, concomitantly with HD at the dose of 0.5 mmol/Kg, 24 hours previously to the sacrifice. After sacrifice, the blood was collected and the aorta removed and mounted in a wire myograph to assess concentration response curves to acetylcholine (ACh) and sodium nitroprusside (SNP). ACh elicited concentration dependent relaxation in aorta of CTL rats, reaching a maximum relaxation of 89 ± 3%, which was significantly reduced in LN group (37 ± 7%). Treatment with HD partially prevented this decrease, reaching the maximum relaxation of 72 ± 2%. On the other hand, SNP induced relaxation was more potent on the aorta of LN (pEC
50
9.67 ± 0.11) when compared to CTL (pEC
50
8.51 ± 0.13) and LNHD rats (pEC
50
8.90 ± 0.09). The oxidative status was not changed by any treatment since SOD activity was 11 ± 1, 9 ± 2 and 12 ± 0.5 U/mL, for CTL, LN and LNHD, respectively and lipid peroxidation measured by TBARS assay showed a MDA concentration of 29 ± 8, 35 ± 7 and 23 ± 3 μM for CTL, LN and LNHD, respectively. Altogether, these data suggest that that Hesperidin prevents the impairment of endothelium-dependent vascular relaxation, through a mechanism not related to its antioxidant property.
Abstract P530: Pleiotropic Effects on Blood Pressure Traits Using Genome-wide Analysis of Gene-alcohol Interactions
Authors: Kraja Aldi T , Feitosa Mary F , Chasman Daniel , Sung Yun J , Winkler Thomas W , Ntalla Ioanna , Aschard Hugues , Rice Kenneth , Manning Alisa K , O’Connell Jeffrey , Kardia Sharon L , Munroe Patricia , Cupples L. Adrienne , Morrison Alana , Gauderman W. James , Levy Daniel , Rao D.C. , Zhu Xiaofeng , Province Michael A , CHARGE Gene-Lifestyle Interactions on behalf of the , the NHLBI grant HL 118305 This work is supported in part by
Published: July 2021

We tested for pleiotropy in European ancestry subjects (N>90K) via GWAS of systolic and diastolic blood pressure (BP), mean arterial pressure, and pulse pressure, using gene (G)-alcohol consumption (E) interactions. The approach was a correlated meta-analysis (PMCID-PMC3773990) that combined simultaneously the 4 BP traits genome-wide GxE interactions summary meta-P values. This approach adjusts for correlations among single traits at the genomic level. A variant was considered pleiotropic when the overall correlated meta-analysis yielded
P
≤5E-08 and GxE meta-
P
≤E-04 for at least two single traits. The novel pleiotropic variants localize in eight loci.
TTLL7
(1p31.1) is a tubulin modifier.
DYRK3
(1q32.1) is a transcription regulator.
MAPKAPK2
(1q32.1) is a stress-activated serine/threonine-protein kinase involved in cytokine production especially for
TNF
,
IL6
and phosphorylates (among others)
LSP1
, identified in our GWAS GxE study for individual BP traits.
FSTL5
(4q32.2) is annotated as
calcium ion binding
. A locus at 11q13.1 includes
SNX32
,
EFEMP2,
and
FOSL1
.
FOSL1
variants may regulate expression of
SNX32
.
EFEMP2
is implicated in blood coagulation.
CATSPER2
(15q15.3) is a cation channel.
CCDC151
(19p13.2) is an outer dynein arm assembly. The functions of two other loci (17q22 and 18q22.3) are unknown. We also identified 4 pleiotropic loci (
SGK223
,
TNKS
,
GATA4
,
FTO
) that were found significant at our GxE meta-GWAS of single traits in 572K multi-ancestry individuals. In addition, we detected 24 pleiotropic BP-known loci. Some of these genes relate to alcohol consumption (e.g.,
BLK
,
GATA4
,
FTO
).
TNKS
,
MAPKAPK2
and
FSTL5
interact with the
Wnt/β-catenin
signaling pathway, which contributes to hypertension. Several pleiotropic variants showed features of regulation by locating at promoter and enhancer histone marks, at DNAse, at proteins binding sites and being eQTL. The 36 novel and BP-known loci comprising 86 significant genes were enriched for
Hypertension
,
Cardiac arrhythmias
,
Myocardial infarction
,
Atrial fibrillation,
and
Left ventricular hypertrophy
. Our correlated meta-analysis of GxE interaction approach identified novel pleiotropic loci and validated known BP loci, thus providing insights into the mechanisms of hypertension.
Abstract P547: Soluble Fiber Diet Alters Cardiovascular Responses To Stress In Normotensive Wky Rats
Authors: Silva Carla G , Yang Tao , Magee Kacy , Malphurs Wendi , Vickroy Thomas , Zubcevic Jasenka
Published: July 2021

Gut microbiota is crucial for function of the gastrointestinal (GI) tract, and modulates the communication between the GI tract and the central nervous system. Microbial metabolites such as propionate have been shown to regulate blood pressure (BP), while butyrate, one of the major bacterial fermented byproducts, reportedly produces beneficial effects in multiple dysbiosis-related diseases. We previously showed that chronic supplementation with soluble fiber-rich, butyrolytic diet modified microbiota and increased BP in the spontaneously hypertensive rat (SHR). Here, we tested the impact of same diet on BP regulation in the Wistar Kyoto rats (WKY).

Methods:
Male 4 weeks old WKY were placed on either the fructooligosaccharides/inulin-rich diet (fiber, N=6), or its calorie-matched control diet (control, N=6) (Research Diets, Inc.) for 14 weeks. Baseline BP was measured by tail cuff every week for the duration of the study, and by telemetry at the end of the study and during 20 minutes of restraint stress. Spectral analysis of BP waveform was performed during restraint stress to measure autonomic variables.

Results:
We observed no significant difference in mean BP measured by tailcuff or by telemetry between the two groups. However, there was an increase in mean BP after 2 minutes of restraint (104.5 ± 7.45 mmHg vs. 116.3 ± 3.19 mmHg; p=0.0411, n=6), which was associated with a trend in increase in LF/HF variable linked with vasovagal balance (1.99 ± 1.43 vs. 3.04 ± 1.46, p=0.17) in the fiber group when submitted to restraint stress.

Conclusion:
Unlike in the SHR, fiber-rich diet did not alter baseline BP in the normotensive WKY. However, chronic fiber diet produced autonomic imbalance and increased BP in response to restraint stress in the WKY.
Patient Selection for Routine Troponin Monitoring After Noncardiac Surgery
Authors: Weersink Corien S. A. , van Waes Judith A. R. , Grobben Remco B. , Nathoe Hendrik M. , van Klei Wilton A.
Published: July 2021

Background

Myocardial infarction is an important complication after noncardiac surgery. Therefore, perioperative troponin surveillance is recommended for patients at risk. The aim of this study was to identify patients at high risk of perioperative myocardial infarction (POMI), in order to aid appropriate selection and to omit redundant laboratory measurements in patients at low risk.

Methods and Results

This observational cohort study included patients ≥60 years of age who underwent intermediate to high risk noncardiac surgery. Routine postoperative troponin I monitoring was performed. The primary outcome was POMI. Classification and regression tree analysis was used to identify patient groups with varying risks of POMI. In each subgroup, the number needed to screen to identify 1 patient with POMI was calculated. POMI occurred in 216 (4%) patients and other myocardial injury in 842 (15%) of the 5590 included patients. Classification and regression tree analysis divided patients into 14 subgroups in which the risk of POMI ranged from 1.7% to 42%. Using a risk of POMI ≥2% to select patients for routine troponin I monitoring, this monitoring would be advocated in patients ≥60 years of age undergoing emergency surgery, or those undergoing elective surgery with a Revised Cardiac Risk Index class >2 (ie >1 risk factor). The number needed to screen to detect a patient with POMI would be 14 (95% CI 14–14) and 26% of patients with POMI would be missed.

Conclusions

To improve selection of high‐risk patients ≥60 years of age, routine postoperative troponin I monitoring could be considered in patients undergoing emergency surgery, or in patients undergoing elective surgery classified as having a revised cardiac risk index class >2.
Targeting Hypertension Screening in Low‐ and Middle‐Income Countries: A Cross‐Sectional Analysis of 1.2 Million Adults in 56 Countries
Authors: Kirschbaum Tabea K. , Theilmann Michaela , Sudharsanan Nikkil , Manne‐Goehler Jennifer , Lemp Julia M. , De Neve Jan‐Walter , Marcus Maja E. , Ebert Cara , Chen Simiao , Aryal Krishna K. , Bahendeka Silver K. , Norov Bolormaa , Damasceno Albertino , Dorobantu Maria , Farzadfar Farshad , Fattahi Nima , Gurung Mongal S. , Guwatudde David , Labadarios Demetre , Lunet Nuno , Rayzan Elham , Saeedi Moghaddam Sahar , Webster Jacqui , Davies Justine I. , Atun Rifat , Vollmer Sebastian , Bärnighausen Till , Jaacks Lindsay M. , Geldsetzer Pascal
Published: July 2021

Background

As screening programs in low‐ and middle‐income countries (LMICs) often do not have the resources to screen the entire population, there is frequently a need to target such efforts to easily identifiable priority groups. This study aimed to determine (1) how hypertension prevalence in LMICs varies by age, sex, body mass index, and smoking status, and (2) the ability of different combinations of these variables to accurately predict hypertension.

Methods and Results

We analyzed individual‐level, nationally representative data from 1 170 629 participants in 56 LMICs, of whom 220 636 (18.8%) had hypertension. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or reporting to be taking blood pressure–lowering medication. The shape of the positive association of hypertension with age and body mass index varied across world regions. We used logistic regression and random forest models to compute the area under the receiver operating characteristic curve in each country for different combinations of age, body mass index, sex, and smoking status. The area under the receiver operating characteristic curve for the model with all 4 predictors ranged from 0.64 to 0.85 between countries, with a country‐level mean of 0.76 across LMICs globally. The mean absolute increase in the area under the receiver operating characteristic curve from the model including only age to the model including all 4 predictors was 0.05.

Conclusions

Adding body mass index, sex, and smoking status to age led to only a minor increase in the ability to distinguish between adults with and without hypertension compared with using age alone. Hypertension screening programs in LMICs could use age as the primary variable to target their efforts.
Association of Socioeconomic Disadvantage With Mortality and Readmissions Among Older Adults Hospitalized for Pulmonary Embolism in the United States
Authors: Wadhera Rishi K. , Secemsky Eric A. , Wang Yun , Yeh Robert W. , Goldhaber Samuel Z.
Published: July 2021

Background

In the United States, hospitalizations for pulmonary embolism (PE) are increasing among older adults insured by Medicare. Although efforts to reduce health disparities have intensified, it remains unclear whether clinical outcomes differ between socioeconomically disadvantaged and nondisadvantaged Medicare beneficiaries hospitalized with PE.

Methods and Results

In this study, there were 53 386 Medicare fee‐for‐service beneficiaries age ≥65 years hospitalized for PE between October 2015 and January 2017. Of these, 5494 (10.3%) were socioeconomically disadvantaged and 47 892 (89.7%) were nondisadvantaged. Socioeconomically disadvantaged adults were of similar age as nondisadvantaged adults (77.1 versus 77.0), more likely to be female (68.5% versus 54.2%), and less likely to receive advanced therapies (11.0% versus 12.1%). After adjustment for demographics, 90‐day all‐cause mortality rates were similar between disadvantaged and nondisadvantaged adults. In contrast, 1‐year mortality rates were higher among socioeconomically disadvantaged adults (hazard ratio [HR], 1.16; 95% CI, 1.10–1.22), although these differences were partially attenuated after additional adjustments for comorbidities and PE severity (HR, 1.09; 95% CI, 1.02–1.16). Risk‐adjusted 30‐day and 90‐day all‐cause readmission rates were substantially higher among socioeconomically disadvantaged patients (30‐day HR, 1.14 [95% CI, 1.06–1.22]; 90‐day HR, 1.18 [95% CI, 1.12–1.25]). In addition, 90‐day readmissions attributed to PE, deep vein thrombosis, and/or bleeding were higher among socioeconomically disadvantaged patients (HR, 1.16; 95% CI, 1.02–1.32).

Conclusions

Socioeconomically disadvantaged older adults hospitalized with PE have higher 1‐year mortality rates compared with their nondisadvantaged counterparts. Nearly 1 in 3 socioeconomically disadvantaged older adults was readmitted within 90 days of a hospitalization for PE. Targeted strategies are needed to improve transitional and ambulatory care for this vulnerable population.
Cardiovascular Development and Congenital Heart Disease Modeling in the Pig
Authors: Gabriel George C. , Devine William , Redel Bethany K. , Whitworth Kristin M. , Samuel Melissa , Spate Lee D. , Cecil Raissa F. , Prather Randall S. , Wu Yijen , Wells Kevin D. , Lo Cecilia W.
Published: July 2021

Background

Modeling cardiovascular diseases in mice has provided invaluable insights into the cause of congenital heart disease. However, the small size of the mouse heart has precluded translational studies. Given current high‐efficiency gene editing, congenital heart disease modeling in other species is possible. The pig is advantageous given its cardiac anatomy, physiology, and size are similar to human infants. We profiled pig cardiovascular development and generated genetically edited pigs with congenital heart defects.

Methods and Results

Pig conceptuses and fetuses were collected spanning 7 stages (day 20 to birth at day 115), with at least 3 embryos analyzed per stage. A combination of magnetic resonance imaging and 3‐dimensional histological reconstructions with episcopic confocal microscopy were conducted. Gross dissections were performed in late‐stage or term fetuses by using sequential segmental analysis of the atrial, ventricular, and arterial segments. At day 20, the heart has looped, forming a common atria and ventricle and an undivided outflow tract. Cardiac morphogenesis progressed rapidly, with atrial and outflow septation evident by day 26 and ventricular septation completed by day 30. The outflow and atrioventricular cushions seen at day 20 undergo remodeling to form mature valves, a process continuing beyond day 42. Genetically edited pigs generated with mutation in chromatin modifier
SAP130
exhibited tricuspid dysplasia, with tricuspid atresia associated with early embryonic lethality.

Conclusions

The major events in pig cardiac morphogenesis are largely complete by day 30. The developmental profile is similar to human and mouse, indicating gene edited pigs may provide new opportunities for preclinical studies focused on outcome improvements for congenital heart disease.
Abstract P020: A Bioengineered Neonatal Cardiomyocyte Scaffold Promotes Cell Survival and Improves Left Ventricular Function in Rats with Heart Failure
Authors: Lancaster Jordan , Juneman Elizabeth , Johnson Nicholle , Bahl Joseph , Goldman Steven
Published: July 2021

Background:
Cell-based regenerative therapies hold promise as a new treatment for heart failure. Tissue engineered scaffolds used for cell delivery enhance potential improvements in cardiac function by providing the structural and nutrient support for transplanted cell survival, integration, and re-population of injured tissues. Previously, our laboratory reported improvements in left ventricular (LV) function in rats with chronic heart failure (CHF) after placement of a neonatal cardiomyocyte (NCM) seeded 3-dimensional fibroblast construct (3DFC). In brief, 3 weeks after implantation of the NCM-3DFC, LV function improves by increasing (p<0.05) ejection fraction 26% and cardiac index 33%, while decreasing (p<0.05) LV end diastolic pressure 38%. The current report focuses on NCM survival and LV improvements out to 7 weeks post NCM-3DFC implantation.

Methods and Results:
Cardiomyocytes were isolated from neonatal rat hearts and seeded onto a 3DFC. We evaluated NCM-3DFC
in vitro
for cellular organization and the presence of functional gap junctions, which demonstrated extensive cell-to-cell connectivity. At 5 days in culture, the seeded patch contracted spontaneously in a rhythmic and directional fashion, beating at 43±3 beats/min with a mean displacement of 1.3±0.3 mm and contraction velocity of 0.8±0.2 mm/sec. The seeded patch could be electrically paced at near physiological rates (270±30 beats/min) while maintaining coordinated, directional contractions. For
in vivo
evaluation, rats underwent coronary artery ligation and allowed to recover for 3 weeks to establish CHF. NCM-3DFC were implanted 3 weeks after ligation and evaluated 3 and 7 weeks later (6 and 10 weeks after ligation respectively). Live cell tracking of implanted NCM using Q-Dots revealed ∼9% survival of transplanted cells 3 weeks after implantation. In addition, improvements in LV function continued at 7 weeks after implantation of the NCM-3DFC by increasing (p<0.05) ejection fraction 37%.

Conclusion:
A multicellular, electromechanically organized, cardiomyocyte scaffold, engineered
in vitro
can improve LV function when implanted directly on the hearts of rats with CHF; the transplanted cells survive and improve LV function chronically.