bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 635: Role of Micro RNA-21 in Venous Neointimal Hyperplasia (VNH): Implications in Targeting MiR-21 For VNH Treatment
Authors: Kialri Sreenivasulu , Yang Binxia , McCall Deborah , Misra Sanjay
Published: July 2021

The exact molecular mechanisms involved in hemodialysis arteriovenous fistula (AVF) failure caused by venous neointimal hyperplasia (VNH) are not clear. It has been observed that there is an accumulation of extracellular matrix and up regulation of pro-fibrotic genes accompanied with presence of fibroblasts, smooth muscle cells, and inflammatory cells in the stenotic veins. Previous studies have demonstrated that adventitial and medial fibroblasts have a pivotal role(s) in VNH formation. MicroRNA-21 (miR-21) contributes to fibroblast to myofibroblast differentiation and dysregulation of miR-21 plays a pathological role in failure of coronary artery bypass grafts. The aim of the present study was to determine the role of miR-21 in VNH associated with AVF. We assessed miR-21 expression using qRT-PCR in the outflow veins of AVFs compared to control (contralateral jugular veins) veins in the C57BL/6J mice with chronic kidney disease (CKD). MiR-21 expression was upregulated accompanied with down regulation of miR-21 target genes; PPAR-α, PTEN and TIMP-3. In addition, gene expression of fibroblast specific protein (FSP) -1, TGF (transforming growth factor) -β1, matrix metalloproteinases (MMP)-2, -9, collagen-I, and IV were significantly increased at day 7 after AVF creation. Immunohistochemistry revealed that there was a significant increase in proliferating cell index (Ki-67) and fibroblast index (FSP-1) in the outflow veins of AVFs. Hypoxia has been shown to increase fibroblast to myofibroblast differentiation and this is predicted to be an early step in VNH formation. Therefore we assessed miR-21 expression in hypoxic (1%O
2
) mouse pulmonary vein fibroblasts compared to normoxic cells
in vitro
and it was found that miR-21and TGF-β1 significantly elevated with down regulation of miR-21 target genes PTEN and TIMP-3. Furthermore, miR-21 knockdown in hypoxic fibroblasts attenuated TGF-β1 expression with a significant upregulation of genes targeted by miR-21 compared to controls. Together these results indicate that upregulation of miR-21 expression may result in fibroblast to myofibroblast differentiation resulting in VNH formation.
Abstract 636: Regulation of Galectin-3 Expression in Pulmonary Vascular Smooth Muscle by Dna Methylation
Authors: Li Xueyi , Chen Feng , Haigh Stephen , Wang Yusi , Bordan Zsuzsana , Stepp David , Weintraub Neal , Barman Scott , Fulton David
Published: July 2021

Pulmonary Arterial Hypertension (PAH) is characterized by excessive vascular cell proliferation, inward remodeling and increased stiffness and inflammation of the pulmonary blood vessels. We found that galectin-3 (Gal-3) is upregulated in PA from multiple models of PAH including monocrotaline (MCT), MCT + pneumonectomy, and SUGEN/hypoxia rats as well as in human PAH and correlated with severity of disease. Gal-3 is a β-galactoside binding lectin implicated in signaling pathways regulating cell proliferation, inflammation and fibrosis, but its role in PAH is poorly defined. Confocal analysis revealed the majority of Gal-3 expression in the media of PA of both rodent models and humans. Selective inhibitors of Gal-3 attenuated PAH in MCT-treated rats and reduced indices of proliferation, fibrosis and increased apoptosis in PA. Overexpression of Gal-3 in PASMC increased proliferation, migration and expression of profibrotic molecules and protected from apoptosis. Acute exposure of cultured HPASMC with various mitogens and factors important in the development of PAH, failed to increase Gal-3 expression. In contrast, PASMC isolated from rats with PAH exhibited an enduring capacity for increased proliferation and expressed higher levels of Gal-3 suggesting an epigenetic mechanism regulating Gal-3 expression. We found that treatment of PASMC with inhibitors of DNA methylation robustly increased Gal-3 expression in control human and rat PASMC but not in MCT-derived PASMC. Methylation analysis of DNA isolated from PA using MeDIP-qPCR and pyrosequencing revealed hypomethylation of Gal-3 proximal promoter. Analysis of DNA methyltransferase expression in PA revealed a significant loss of only Dnmt3A expression in hypertensive PA. To assess the role of local methylation in the regulation of Gal-3 expression we used CRISPR-dCas9. Targeted Gal-3 promoter methylation using multiple RNA guides and dCas9-Dnmt3A-Dnmt3L effectively reduced Gal-3 expression in SMC isolated from MCT rat PA and reversed the excessive proliferation. These results advance an important role of methylation-dependent mechanisms in Gal-3 signaling and provide a mechanism for the enduring changes in vascular cell behavior observed in PAH.
Abstract 640: Overexpression of Vasohibin-2 Exacerbates Development of Angiotensin II-Induced Thoracic Aortic Aneurysms Independent of VeEGF
Authors: Okuyama Michihiro , Uchida Haruhito A , Umebayashi Ryoko , Kakio Yuki , Takeuchi Hidemi , Tanabe Katsuyuki , Sato Yasufumi , Wada Jun
Published: July 2021

Objective:
Chronic angiotensin II (AngII) infusion promotes both thoracic (TAAs) and abdominal aortic aneurysms (AAAs) in mice. Vasohibin-2 (VASH2) is known to cause angiogenesis at the sprouting front of neovascularization. The purpose of this study was to examine whether VASH2 influenced AngII-induced TAAs.

Methods:
Male C57BL/6J mice (10-week-old) were injected with VASH2 or LacZ expressing adenovirus (Ad; 7.5 x 10
9
vp/100 μL) via tail vein at 2 week intervals. One week after the first injection, subcutaneous infusion of either AngII (1,000 ng/kg/min) or saline by mini osmotic pumps was started for 3 weeks. Consequently, mice were divided into 4 groups: AngII + Ad VASH2 (n=22), AngII + Ad LacZ (n=21), saline + Ad VASH2 (n=10), saline + Ad LacZ (n=8). Next, in order to examine whether VASH2 affected TAAs via VEGF regulation, bevacizumab was intraperitoneally administrated into mice; AngII + Ad VASH2 + saline (n=15), AngII + Ad VASH2 + bevacizumab (n=15). TAAs were evaluated in all mice by
en face
method. Third, human aortic smooth muscle cells (hSMCs) were infected with Ad VASH2 or Ad LacZ, stimulated with or without AngII to evaluate further mechanism.

Result:
Intima area of aortic arch was significantly larger in AngII + Ad VASH2 group than in AngII + Ad LacZ group (19.78 ± 0.40 mm
3
vs 17.74 ± 0.44 mm
3
, P < 0.001). Gelatin zymography demonstrated that AngII upregulated latent MMP-2 expression, and activated MMP-2 most prominently in AngII + VASH2 group. Protein expression of p21 and p53 in thoracic aortas was enhanced in AngII + VASH2 group. Positive TUNEL staining was observed in thoracic aortic wall of AngII + VASH2 group. No significant difference in intima area of aortic arch between AngII + Ad VASH2 + saline group and AngII + Ad VASH2 + bevacizumab group. In vitro, the same results were observed regarding protein expression of p21 and p53, and TUNEL staining. In addition, Annexin-V staining was detected only in AngII + VASH2 group.

Conclusion:
Overexpression of VASH2 accelerated development of AngII-induced TAAs in vivo. VASH2-induced cell apoptosis may influence AngII-induced TAA formation independent of VEGF.
Abstract 642: Specific Protein Kinase C Isoforms Are Critical Mediators of Physiologic Downregulation of Perivascular Tissue Factor
Authors: Sommerville Laura , Gorman Kristen , Monroe Dougald , Hoffman Maureane
Published: July 2021

Tissue factor (TF) is a procoagulant and transmembrane receptor for FVII(a) that is upregulated in pathological conditions. We recently demonstrated that perivascular TF is downregulated around angiogenic vessels near a cutaneous wound. The goal of this study was to identify mechanisms that mediate TF loss. Primary cultures of human pericytes express high levels of TF. TF expression was lost during culture with phorbol-12 myristate 13-acetate (PMA) for 8 hours, and was maintained for 24 hours. This model recapitulates the pattern of downregulation observed
in vivo
. Using qRT-PCR we assessed changes in TF gene expression in response to PMA. TF mRNA decreased 4- and 6-fold at 8 and 12 hours after treatment (p<0.01), and remained 2-fold lower in treated cells after 24 hours (p<0.05). Inhibiting
de novo
transcription with actinomycin D showed that degradation of TF mRNA was similar in PMA- and vehicle-treated groups (p=ns). Thus, downregulation of TF mRNA occurs primarily through inhibition of its synthesis. We next identified a physiologic mediator of TF downregulation using specific inhibitors against PMA-responsive signaling proteins. Two different inhibitors against Protein Kinase C (PKC) were used: Go6983, which inhibits isoforms α, β, δ, ε, μ, and ζ, and GFX, which inhibits α, β, ε, and γ. Both inhibitors significantly attenuated PMA-mediated transcriptional downregulation (p<0.001). Based on overlap of inhibited isoforms, this suggests a minimal role for ζ, μ, δ, and γ, while one or more of the α, β, and ε isoforms appear to be critical mediators of TF mRNA synthesis inhibition. Since the timing of TF protein loss is not fully explained by transcriptional inhibition, we investigated the role of protein degradation in TF loss. When protein synthesis was inhibited by cyclohexamide, addition of PMA shortened the half-life of pericyte TF from 11 hours to 5 hours (p<0.001). This indicates that increased protein degradation contributes to PMA-induced loss of TF expression. Both Go6983 and GFX significantly attenuated TF protein degradation also. Taken together, our data show that TF downregulation is mediated by transcriptional inhibition and protein degradation, and PKC α, β, and ε have emerged as potential mediators of both mechanisms.
Abstract 7:
In vivo
Transcriptional Profiling of Endothelial Cells Identifies Vascular Bed-Specific Changes Upon Lps-Induced Endotoxemia
Authors: Cleuren Audrey , van der Ent Martijn , Hunker Kristina , Jiang Hui , Yee Andrew , Siemieniak David , Ganesh Santhi , Ginsburg David
Published: July 2021

Endothelial cells (ECs) form a critical barrier between blood and parenchymal cells and play an important role in many pathologic conditions, including sepsis. ECs are highly adaptive to their microenvironment and also act as a critical responder to microbial pathogens. Though ECs are thought to display extensive heterogeneity, detailed profiling of the
in vivo
EC gene expression program has been limited by the challenges of isolating ECs from complex tissues and the phenotypic drift associated with manipulation and expansion of ECs
in vitro
. We applied an
in vivo
system in which a conditional hemagglutinin-epitope tag is targeted into the mouse ribosomal protein
Rpl22
locus and specifically activated in ECs, allowing immunoisolation of endothelial ribosome-associated mRNA. Both EC-selected and total mRNA from tissue lysates (brain, heart, kidney, liver and lung) were subjected to RNA sequencing followed by differential expression analysis to determine EC-enriched transcripts. These analyses were performed under physiologic conditions as well as in LPS injected mice to study transcriptional changes induced in ECs following endotoxin exposure. LPS-induced endotoxemia resulted in striking changes in the EC transcriptome (~800 per tissue), and included transcripts associated with known sepsis related pathophysiology, including impaired hemostasis, leukocyte recruitment and increased vascular permeability. Gene ontology analysis of transcriptional changes shared between ECs of different tissues identified cellular response to LPS among the highest enriched biologic processes (adjusted p-value 5.2E-5), together with immune (2.0E-14) and inflammatory responses (4.4E-12). Novel transcripts not previously associated with ECs or endotoxemia were also identified, as well as a subset of genes uniquely expressed in distinct vascular beds. In conclusion, our findings demonstrate remarkable heterogeneity of the EC transcriptome across multiple vascular beds
in vivo
. The EC response to endotoxin challenge is also highly heterogeneous across vascular beds and provides new insight into the endothelial response to infectious challenges, as well as identifying potentially useful biomarkers for the onset of sepsis and response to therapy.
Abstract 94: Deficiency of Epsins in Macrophages Ameliorates Atherosclerosis by Attenuating Inflammation
Authors: Brophy Megan L , Dong Yunzhou , Wu Hao , Song Kai , Rahman Ashiqur , Wen Aiyun , Kwak Sukyoung , Wong Scott , Krygier Kenneth , Ley Klaus , Chen Hong
Published: July 2021

Background:
Atherosclerosis is caused by the immune and inflammatory cell infiltration of the vascular wall, leading to enhanced inflammation and lipid accumulation. Understanding the molecular mechanisms underlying this disease is critical for the development of new therapies. Our recently studies demonstrate that endothelial epsins, a family of ubiquitin-binding endocytic adaptors are critical regulators of atherosclerosis. However, whether epsins in macrophages play a role in regulating vascular inflammation is unknown. We hypothesize that epsins in macrophages promote inflammation to facilitate atherogenesis.

Methods and Results:
We engineered myeloid cell-specific epsins double knockout mice (MΦ-DKO) on an ApoE-/- background fed western diet. Strikingly, these mice exhibited reduced atherosclerotic lesion formation, diminished immune and inflammatory cell recruitment to aortas and reduced cleaved caspase 3 staining but increased α-SMA staining within aortic root sections. Epsin deficiency hindered foam cell formation, suppressed the pro-inflammatory M1 macrophage phenotype but increased the anti-inflammatory macrophage phenotype, and enhanced efferocytosis in primary macrophages. Mechanistically, we show that epsin loss specifically increases total and surface levels of LRP-1, a protein with anti-inflammatory properties without altering levels of LDL scavenger receptors. We further show that epsin and LRP-1 interact via epsin’s UIM domain. Oxidized LDL treatment increased LRP-1 ubiquitination and subsequent binding to epsin while mutation of cytoplasmic lysine residues attenuated LRP-1 ubiquitination, suggesting that epsin promotes the ubiquitin-dependent internalization and degradation of LRP-1. Importantly, MΦ-DKO/ApoE null mice on LRP-1 heterozygous background restored atherosclerosis, suggesting that epsin-mediated LRP-1 downregulation in macrophages plays a pivotal role in propelling atherogenesis.

Conclusions:
Macrophage epsins promote atherogenesis, in part, by facilitating pro-inflammatory macrophage recruitment and potentiating foam cell formation by downregulating LRP-1, implicating that targeting epsin in macrophages may serve as a novel therapeutic strategy to treat atheroma.
Abstract 96: Melatonin Prevents Atherosclerosis via Regulating NLRP3 Inflammasome: The Role of Sirt3 Signaling
Authors: Ma Sai , Chen Jiangwei , Luo Zhenli , Wang Yabin , Cao Feng
Published: July 2021

Introduction:
NLRP3 inflammasome mediated inflammatory factors secretion is critically involved in atherosclerosis (AS). Melatonin has anti-inflammatory properties. However, it is unknown whether melatonin is beneficial in AS.

Hypothesis:
Melatonin plays a beneficial role in AS by decreasing NLRP3 inflammasome activation in macrophages.

Methods:
AS model was induced with high fat diet in apoE
-/-
mice. Plaque stability was examined with historical staining.
In vitro
study was performed in ox-LDL treated RAW264.7 cells. NLRP3 inflammasome activation, inflammatory factors secretion, mitochondrial ROS generation, autophagy, mitophagy indexes and potential signaling pathways were investigated.

Results:
Historical staining results showed that melatonin treatment markedly alleviated AS plaque progression. Despite of unchanged protein expression, Sirt 3 activity was elevated in plaque tissue in melatonin treated mice. Melatonin attenuated NLRP3 inflammasome activation and inflammatory factors secretion in ox-LDL treated macrophages, while this protective effect was abolished by Sirt3-siRNA. Mitochondrial ROS (mitoROS), which was an inducer for NLRP3 inflammasome, was reduced by melatonin through the elimination of damaged mitochondria (mitophagy). Similar with Sirt3-siRNA, autophagy inhibitor 3-MA also abolished the effects of melatonin on mitoROS clearance, indicating the crucial role of autophagy and mitophagy in melatonin caused NLRP3 inactivation. Furthermore, melatonin protected against AS via Sirt3/FoxO3/Parkin signaling pathway.

Conclusions:
Melatonin prevented atherosclerotic progression. Melatonin reduced mitochondrial ROS through the activation of autophagy and mitophagy, thereby attenuating NLRP3 inflammasome activation in macrophages. Moreover, the protective effect of melatonin was mediated by Sirt3/FoxO3/Parkin signaling pathway. Our study provides insight into a new therapeutic target for AS.
Abstract 6108: Cardiac 64-slice Multidetector Computerized Tomography in the Management of Prosthetic Heart Valve Obstruction
Authors: Gündüz Sabahattin , Duran Nilüfer E , Biteker Murat , Güneysu Tahsin , Gökdeniz Tayyar , Astarcioǧlu Mehmet A , Ertürk Emre , Aykan Ahmet Ç , Yildiz Mustafa , Özkan Mehmet
Published: July 2021

Differentiation of pannus (P) and thrombus (THR) in prosthetic heart valve obstruction (PHVO) is still a confusive state at the present cardiological practise. Transesophageal echocardiography (TEE) is not fully capable method in this condition. We considered that cardiac 64-slice multidetector computerized tomography (MDCT) may have a value in the management of PHVO. Thirtytwo of 37 pts (22 male, mean age 47±11 years, 17 with atrial fibrillation) with PHVO (35 mitral, 2 tricuspid) were detected with TEE and also with MDCT before and after thrombolytic therapy (TT). Five pts having monoleaflet valves were excluded due to excessive artifacts. Pre-TT MDCT revealed at least 1 culprit mass (CM) which was considered to be the cause of PHVO and the Hounsfield unit (HU) values of CM’s were measured. All pts underwent TT under the guidance of serial TEE. The study consisted of 2 groups up to response of CM’s to TT demonstrated by post-TT MDCT. Group I: Successfully lysed CM’s, Group II: Nonresponder CM’s. TEE disclosed THR in 26 pts, however the cause of PHVO in 6 pts remained undefined. Pre-TT MDCT disclosed 45 distinct CM’s on 32 valves. Post-TT MDCT disclosed the number of CM’s for groups I and II: 26 and 19, respectively. Significant difference between mean HU values of groups was found [87 (range 11–180), 331 (range 168–510), respectively, p<0.001]. A cut-off value of HU>200 predicted nonresponder CM’s (sensitivity 94%, specificity 96%, p<0.001). CM’s of 6 pts with undefined TEE findings were all in group II and pure P was demonstrated surgically. In group I, 17 of 26 (%65) CM’s were completely and the remaining partially lysed which was confirmed by TEE. A cut-off value of HU<100 predicted complete lysis (sensitivity 100%, specificity %95, p<0.001). Subgroup analysis of CM’s with HU=100–200 revealed 10% completely and 80% partially lysis and 10% remained unresponded as confirmed by TEE. MDCT can be a useful technique for evaluation of PHVO caused by THR or P formation. Higher HU values denote P whereas the lower values THR. MDCT can also predict the response to TT. The higher the HU value the less the successful outcome. The CM’s with HU>200 are almost always resistant to TT.
Abstract 4984: Trends in 10-year Risk of Incident Cardiovascular Disease in the United States, 1972–2004
Authors: Lopez-Jimenez Francisco , Batsis John A , Ting Henry H , Somers Virend K
Published: July 2021

Background
: The significant bidirectional changes in cardiovascular(CV) risk factor prevalence make the net trend in incident CV risk unknown. We assessed the trends in the net 10-year risk for incident CV disease using the Framingham risk model and data from the National Health and Nutrition Examination Surveys(NHANES).

Methods
: We used data from NHANES II (1976–1980), NHANES III (1988–1994), and NHANES 1999–2004, including major CV risk factors, all collected in a standardized manner. People with a history of CV disease, pregnant women, people with missing data and those outside the Framingham age range were excluded. The Framingham risk function estimated the 10-year risk for CV disease. The slope of change or rate of change per year between NHANES II/III, and between NHANES III/1999–2004 were determined. The slope difference was calculated and compared to zero.

Results
: The mean age-adjusted 10-year CV risk decreased from 10 to 7.9% between NHANES II and III, with a significant slope (p<0.001). However, the mean age-adjusted risk decreased to a lesser extent between NHANES III and NHANES 1999–2004 from 7.9 to 7.4% (p<0.001). The slopes were different (p<0.001). In women, CV risk did not change between NHANES III and 1999–2004, 7.9 to 7.5%, (p=0.40). Predicted 10-year risk by age group (Figure

) shows that the decrease in CV risk was lower in the second period compared to the first one in all age groups, except in the elderly.

Conclusion
: The estimated net risk for CV disease in the US population decreased from 1976–1980 to 1988–1994 but minimally changed from 1988–1994 to 1999–2004, particularly in women. The increased prevalence of obesity may have offset the gain in CV risk reduction.

Predicted 10-year Framingham Risk by Age Group
Abstract 4715: Diagnostic Accuracy of Non-invasive 64-row Computed Tomographic Coronary Angiography (CCTA) Compared with Myocardial Perfusion Imaging (MPI): The PICTURE Study, A Pospective Multicenter Trial
Authors: Budoff Matthew J , Kazerooni Ella A , Thomas Gregory S , Mieres Jennifer H , Shaw Leslee J
Published: July 2021

Although multiple studies have shown excellent accuracy statistics for non-invasive angiography by 64-CCTA, most studies comparing nuclear imaging with CCTA were performed on patients already referred for cardiac catheterization, introducing verification and referral bias. This prospective trial evaluated the diagnostic accuracy of 64-row CCTA to detect obstructive coronary stenosis compared to MPI, using quantitative coronary angiography (QCA) as a reference standard.

Methods:
12 sites prospectively enrolled 230 patients (pts) [52% male, 56.9 yrs] with chest pain who were referred for MPI to assess CAD. To date, 48 patients were clinically referred for invasive coronary angiography (ICA) for either positive MPI or abnormal CCTA. All Pts underwent both MPI and CCTA (Lightspeed VCT/Visipaque 320, GE Healthcare) prior to ICA. CCTAs were graded on a 15-segment AHA model by 2 blinded readers for presence of obstructive stenosis (≥50% or ≥70%); MPI was graded by 2 blinded readers using a 17 segment model for estimation of the % myocardium ischemic or with stress defects. ICAs were independently graded for % stenosis by QCA. Efficacy of MPI and CCTA were assessed including all vessel segments for per-patient and per-vessel analyses.

Results:
Prevalence of stenosis ≥50% by ICA was 52.1% (25/48). The diagnostic accuracy (per-patient analysis) of CCTA and stress MPI compared to ICA are reported in Table 1

. For ≥50% stenosis, the CTA odds ratio for ICA disease was 51.75 (95% CI=8.50–314.94). For SSS ≥5%, the odds ratio for ICA CAD was 12.73 (95% CI=2.43–66.55). Using ROC curve analysis, CCTA was better at classifying obstructive CAD when compared to MPI (Area=0.87 vs. 0.76, p<0.0001).

Conclusions:
This study represents the first prospective multicenter data comparing 64-row CCTA to MPI, demonstrating high diagnostic accuracy of CCTA to reliably detect >50% and >70% stenosis in chest pain patients.

Diagnostic Accuracy Statistics for Coronary Computed Tomographic Angiography (CTA) and Stress Myocardial Perfusion Imaging (MPI) SPECT in Patients Prospectively Enrolled in the PICTURE Trial
Abstract 11427: Ethnic Differences in Factors Precipitating Hospital Admissions for Heart Failure in Middle-Eastern Arabs and South Asians: Insights From the Gulf CARE Registry
Authors: Salam Amar M , Sulaiman Kadhim , Bonow Robert O , Al-Suwaidi Jassim , AlHabib Khalid , Almahmeed Wael , Alsheikh-Ali Alawi , Panduranga Prashanth , AlFaleh Husam , Elasfar Abdelfatah , Al-Motarreb Ahmed , Bazargani Nooshin , Ridha Mustafa , Bulbanat Bassam , Al-Jarallah Mohammed , Amin Haitham , Asaad Nidal , Al-Qahtani Awad , Singh Rajvir ,   The Gulf aCute heArt failuRe rEgistry (Gulf CARE)Study Investigators, Yacoub Magdi
Published: July 2021

OBJECTIVES:
No previous studies have specifically examined the effects of ethnicity on factors precipitating hospital admissions for heart Failure (HF). The aim of the current study was to identify factors precipitating HF hospitalizations peculiar to Middle-Eastern Arab and South Asian ethnicities using a large multinational multicenter Middle-Eastern HF registry in which these two ethnicities are most prevalent.

METHODS:
From February 2012 to November 2013, consecutive patients hospitalized with HF were enrolled from 47 hospitals in 7 Middle East countries. Identifiable factors contributing to HF hospitalization were pre-specified and captured at admission. Patients were divided into 2 groups according to ethnicity, Arabs and South Asians (referred to as Asians) and the 2 groups were compared.

RESULTS:
During the study period 5005 patients with HF were enrolled of whom 4989 patients were from the 2 ethnicities under study; 4516 Arabs (90.5%) and 473(9.5%) Asians with the mean age of 60 years for Arabs and 55 years for Asians. The mean left ventricular ejection fraction was 37 % for Arabs compared to 33.8 % for Asians, P=0.001. Among the precipitating factors studied, nonadherence to medications and infections were significantly more prevalent in Arabs compared to Asians (19.9% vs. 13.5% and 15.3% vs.8.5%, both P=0.001) whereas myocardial ischemia and uncontrolled hypertension were significantly more prevalent in Asians (40.4% vs. 25.9% and 11.6% vs.7.8%, both P=0.001). In both groups, however, myocardial ischemia and nonadherence to medications were the commonest two factors precipitating hospital admissions for HF (table).

CONCLUSIONS:
Our study identifies for the first time important ethnic related differences in precipitating factors for HF hospitalizations among Arabs and Asians living in the Middle-East. The current study underscores the need to consider ethnicity in studies of HF hospitalizations and HF outcomes.
Abstract 12503: Synchrotron Radiation Coronary Microangiography for Evaluating Changes in the Caliber of the in vivo Rat Coronary Artery After Endothelin Administration
Authors: Sakamoto Hiroaki , Matsushita Shonosuke , Hyodo Kazuyuki , Tokunaga Chiho , Sato Fujio , Hiramatsu Yuji
Published: July 2021

Background:
Conventional coronary angiography can visualize vessels of 300 μm in diameter, but not those of smaller diameter, such as the proliferating collateral arteries of ischemic heart disease and the new blood vessels formed in regenerative medicine. We have developed a system of synchrotron radiation coronary microangiography (SRCA) in the in vivo rat. The purpose of this study was to define the minimum detectable caliber change in the coronary arteries of the in vivo rat by inducing vasoconstriction with endothelin during SRCA.

Method:
SRCA was performed at the Photon Factory of the High Energy Accelerator Research Organization (Tsukuba, Japan). The advantages of synchrotron radiation derived X-rays are high spatial resolution (5 μm/pixel) due to increased photon density and straightness of beam. High density resolution is obtained with a high-gain avalanche rushing amorphous photoconductor camera using a fiber-optic plate. Rats were anesthetized. The polyethylene tube for angiography was inserted into the carotid artery. SRCA was performed before and after endothelin administration.

Results:
The electrocardiography showed ST elevation after endothelin administration. High spatial and density resolution images were obtained. Figures A and B show the changes in the caliber of the coronary arteries: Figure A shows the arteries before endothelin administration, and Figure B shows them after endothelin administration. The minimum identified coronary artery diameter in the in vivo rat was 65 μm, and the minimum detectable caliber change was 20 μm.

Conclusion:
The SRCA system could confirm the microvascular constriction of the coronary arteries in the in vivo rat after endothelin administration. We plan next to use SRCA to evaluate endothelial dysfunction in diabetic rats. SRCA may aid investigation of collateral artery proliferation in ischemic heart disease and new blood vessel formation in regenerative medicine in the near future.
Abstract 12737: Physiological Balance Between Nitric Oxide and Endothelium-Derived Hyperpolarizing Factor Plays a Crucial Role in Cardiovascular Homeostasis
Authors: Godo Shigeo , Saito Hiroki , Sawada Ayuko , Sato Saori , Tanaka Shuhei , Shimokawa Hiroaki
Published: July 2021

Background:
The endothelium modulates vascular tone by synthesizing and releasing endothelium-derived relaxing factors (EDRFs), including prostacyclin, nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHFs). The contribution of each EDRF to endothelium-dependent vasodilatation varies depending on the vessel size; conduit arteries are primarily regulated by NO and resistance arteries by EDHFs, regardless of species and blood vessels tested. We have recently demonstrated that caveolin-1 (Cav-1), which functionally inhibits the activity of endothelial NO synthase (eNOS), is substantially involved in the functional inhibition of eNOS in resistance vessels in mice. However, the significance of the physiological balance between NO and EDHF in cardiovascular homeostasis remains to be elucidated.

Methods and Results:
We used 3 genotypes of mice including wild-type (WT), Cav-1-knockout (Cav-1-KO) and endothelium-specific eNOS transgenic (eNOS-Tg) mice; in the latter 2 genotypes eNOS activity is genetically up-regulated. Isometric tension experiments showed that in small mesenteric arteries from both Cav-1-KO and eNOS-Tg, NO-mediated relaxations were significantly enhanced, whereas EDHF-mediated responses were markedly reduced (n=7 each). Langendorff experiments also showed that EDHF-mediated coronary flow responses were significantly reduced in both Cav-1-KO and eNOS-Tg (n=6 each). Furthermore, both genotypes showed altered cardiovascular phenotypes, including hypotension in eNOS-Tg and cardiac hypertrophy in Cav-1-KO. Finally, we examined the cardiac responses to chronic pressure overload by transverse aortic constriction (TAC). Both Cav-1-KO and eNOS-Tg showed reduced survival rate after TAC, associated with more progressive left ventricular systolic dysfunction and more reduced coronary flow reserves as compared with WT (n=15 each).

Conclusions:
These results indicate that the physiological balance between NO and EDHFs plays a crucial role in cardiovascular homeostasis in mice in vivo.
Abstract 13675: The Impact of Major Vascular Complications on the Long-Term Outcome for Patient Undergoing Trans-Catheter Aortic Valve Replacement
Authors: Minha Sa’ar , De Magalhaes Marco , Escarcega Ricardo O , Barbash Israel M , Baker Nevin C , Ben-Dor Itsik , Pendyala Lakshmana K , Ota Hideaki , Lhermusier Thibault , Tian Wenjie , Chen Fang , Okubagzi Petros G , Pichard Agusto D , Suddath William O , Satler Lowell F , Torguson Rebecca , Waksman Ron
Published: July 2021

Introduction:
Major vascular complications (MjVC) of TAVR are associated with poor long term outcome. Since in-hospital mortality is included in the 2nd Valve Academic Research Consortium definitions of MjVC, the long term outcome of patients that had MjVC and survived to discharge and 30 days is less clear.

Hypothesis:
It is hypothesized that the MjVC is associated with long term mortality even if patients survived the first 30 days post-TAVR as compared to patients with no vascular complication (NVC) or those that had minor vascular complications (MiVC).

Methods:
392 patients that underwent trans-femoral TAVR were included. A comparison was completed between patients that had NVC (n=266), MiVC (n=88) and MjVC (n=38). Survival estimate included a landmark analysis capped at 30 days post-TAVR.

Results:
No differences were noted in the baseline characteristics of patients with MjVC, MiVC or NVC (Age 85.2±4.8,82.9±7.3,82.5±8.6;p=0.05,STS score 10.1±3.7 vs. 9.4±4.1 vs. 9.1±4.6;p=0.4, ejection fraction 52.8±13.6% vs. 52.2±13.1 vs. 53.1±14.1;p=0.8 respectively) . Patients that had MjVC had longer hospitalization (10.4±7.3 vs. 5.7±3.6 vs. 6.3±5.2 days; p<0.001 respectively), higher rate of infections (36.8% vs. 6.8% vs. 9.4%;p<0.001 respectively)and higher rate of post-TAVR transfusions (82.6% vs. 47.7% vs. 25.6%;p<0.001 respectively). These differences translated into long-term higher mortality risk for patients sustaining MjVC even after surviving to 30 days post-TAVR (figure).

Conclusions:
MjVC continues to be associated with poor outcome after TAVR even if patients survived to 30 days. This might be related to the procedural and post-procedural complication and not to the baseline characteristics of the patient and thus these patients should be subjected to special surveillance and care.
Abstract 16028: Sustained Increase in the Incidence of Acute Cardiovascular Events After the 2011 Northeast Japan Tsunami: A Population Based Study
Authors: Nakamura Motoyuki , Tanaka Fumitaka , Honma Miho , Komi Ryosuke ,   Iwate Heart Disease Registry Consortium
Published: July 2021

BACKGROUD:
No population based studies to date have reported the long-term effects on the incidence of acute myocardial infarction (AMI) and acute decompensated heart failure (DHF) after a devastating tsunami.

METHODS:
A population based AMI and DHF registration study was conducted in the Iwate prefecture 2 years before and 2 years after the 2011 Japan earthquake and tsunami. Clinical records were reviewed at all hospitals within the district and at nearby teaching hospitals. AMI including sudden cardiac death and DHF were then registered according to the MONICA criteria, and the Framingham definition, respectively.

RESULTS:
During the 4 year survey period, a total of 1,223 AMI cases (mean age = 74.5) and 1,416 DHF cases (mean age = 80.1) were identified. The standardized incidence ratio (SIR) and 95% CI for AMI and DHF during the disaster year of 2011 and the post disaster year of 2012 were determined respectively from the number of observed cases relative to the number of expected cases calculated by age adjusted incidence rates for two pre disaster years (2009-2010). When the SIR of AMI and DHF were compared between the control area and the tsunami stricken area (Figure), ratios for both AMI and DHF were significantly higher in the tsunami stricken area in the disaster year of 2011(AMI; 1.24, 95% CI 1.08 - 1.42: DHF; 1.58, 95% CI 1.43 - 1.74), and this increase was sustained even in the post disaster year of 2012 (AMI; 1.24, 95% CI 1.08 - 1.43: DHF; 1.28, 95% CI 1.15 - 1.43). However, in the control area with no significant tsunami damage, no such increase was apparent during the disaster year or the post disaster year.

CONCLUSION:
After the devastating tsunami, the incidence of AMI and DHF increased significantly and this increase was sustained for more than a year. This suggests that sudden drastic changes in daily life due to devastating natural disasters increase the incidence of acute cardiovascular events in a sustained manner
Abstract 004: The Cost-Effectiveness of Blood Pressure Control in Young Adulthood to Prevent Later Life Coronary Heart Disease: A Computer Simulation Study
Authors: Singh Sonia , Kohli-Lynch Ciaran , Zhang YiYi , Thanataveerat Anusorn , Vittinghoff Eric , Pletcher Mark J , Bibbins-Domingo Kirsten , Moran Andrew E
Published: July 2021

Introduction:
Prehypertension defined as blood pressure (BP) 120-139/80-89 mmHg, has a prevalence of 23% in U.S. young adults (age 20-39 years). Young adult high diastolic blood pressure (DBP) has been associated with later life coronary heart disease (CHD), but it is unclear if lifelong benefits of early blood pressure control outweigh costs and side-effect risks.

Objective:
We estimated CHD events and life-long cost-effectiveness of U.S. Preventive Service Task Force recommended lifestyle modification (LM) or pharmacotherapy in young adults with DBP ≥80mmHg, incremental to later life hypertension treatment.

Methods:
A microsimulation model simulated CHD events from age 20 until death for 20-year olds selected from 1999-2014 NHANES. Individual risk factor trajectories were assigned, and risk functions predicted CHD based on Framingham Offspring Study data, accounting for both age 20-39 time-weighted average DBP and later life systolic blood pressure (SBP). Simulated interventions lowered DBP ≥80mmHg for age 20-39 years, and SBP ≥140mmHg for age ≥40 years. Cost-effectiveness was measured as incremental cost-effectiveness ratios (ICERs) and net health benefit (NHB) at willingness to pay (WTP) threshold $50,000/quality adjusted life year (QALY).

Results:
In 40,000 young adults with DBP ≥80 mmHg (50% women), pharmacologic BP control in young adulthood and later life prevented the most CHD events (Table). The strategy that yielded highest NHB in women was pharmacologic control after age 40 (ICER $26,536/QALY). In men, lifestyle modification to control DBP in young adulthood plus pharmacotherapy for later life hypertension (ICER $42,481/QALY) yielded highest NHB.

Conclusion:
Early DBP control in young adults could achieve substantial health benefits over the life course but standard interventions to achieve this goal are costly. Innovative strategies to reduce pharmacotherapy costs and improve sustainability of lifestyle modification could make early BP control a higher-value prevention strategy in young adults.
Abstract 006: Role of Providers in Implementation of Blood Pressure Control Strategies in Patients with Hypertension
Authors: Mills Katherine T , Obst Katherine M , Shen Wei , Molina Sandra , Zhang Hui-Jie , He Hua , He Jiang
Published: July 2021

Introduction:
Globally, only 13.8% of hypertensive patients have their blood pressure (BP) controlled. Trials testing implementation strategies to overcome barriers to BP control have produced mixed results. Providers who deliver the intervention may play an important role in implementation strategy success. This meta-analysis aimed to determine which provider-led interventions are most effective for BP reduction.

Methods:
We searched Medline and Embase (through September 2017) for randomized controlled trials of various provider-led implementation strategies targeting barriers to hypertension control in hypertensive patients. Seventy-four trials with 22,180 hypertensive participants met our eligibility criteria and were included in this analysis. These trials were grouped by intervention provider, and the effects of the intervention on BP change were combined using random effects models.

Results:
Pharmacist-led health coaching and team-based care had the greatest reduction in systolic and diastolic BP. Nurse- and community health worker-led interventions also resulted in significant reductions in BP. Interventions led by multiple providers were less effective for BP reduction. Research staff-led interventions were also effective at reducing BP but questions of sustainability persist.

Conclusions:
Pharmacists are most effective for the delivery of implementation strategies for BP control among patients with hypertension. Nurse- and community health worker-led interventions were also effective for BP reduction. Pharmacist-, nurse- and community health worker-led interventions should be prioritized in future BP control efforts.
Abstract 010: Prevention of Chronic Kidney Disease: Impact of Addressing the Blood Pressure Distribution, Not Just the Tail
Authors: Hardy Shakia T , Avery Christy L , Zeng Donglin , Kshirsagar Abhijit V , Viera Anthony J , Heiss Gerardo
Published: July 2021

Background:
While much of the chronic kidney disease (CKD) literature focuses on the role of blood pressure reduction in delaying CKD progression, little is known about the benefits of modest population-wide decrements in blood pressure on incident CKD.

Methods:
We used multivariable linear regression to estimate incidence rate differences comparing the impact of 2 pragmatic hypothetical interventions to reduce the incidence of CKD: (1) a population-wide intervention that reduced systolic blood pressure by 1 mmHg and (2) targeted interventions that reduced the prevalence of unaware, untreated, or uncontrolled blood pressure above goal (as defined by Joint National Committee (JNC) 7 and JNC 8 thresholds) by 10%. The population comprised 15,390 participants of the Atherosclerosis Risk in Communities Study (45-64 years of age at baseline, 1987-1989). Incident CKD was ascertained from laboratory assays and abstraction of medical records.

Results:
Over a mean of 20 years of follow up, 3,852 incident CKD events were ascertained. After adjustment for antihypertensive use, gender, diabetes, and age a 1 mmHg decrement in SBP across the total population was associated with an estimated 11.7 and 13.4 fewer incident CKD events per 100,000 person-years (PY) in African Americans and white Americans, respectively. Among participants with blood pressure above JNC 7 goal, a 10% decrease in unaware, untreated, or uncontrolled blood pressure was associated with 3.2, 2.8 and 5.8 fewer incident CKD events per 100,000 PY in African Americans and 3.1, 0.7, and 1.0 fewer incident CKD per 100,000 PY in white Americans. Interventions targeted to the population with blood pressure above JNC 7 goal produced greater reductions in incident CKD than interventions targeted at reductions in blood pressure above JNC 8 treatment goal. Extrapolation to the US African American and white American populations age greater than 45 years (NHANES 2010) suggests that a 1 mmHg decrement in SBP could result in approximately 9,996 fewer incident CKD events annually compared to approximately 2,098, 636, and 1,598 fewer incident CKD events potentially preventable from 10% decreases in unaware, untreated, and uncontrolled blood pressure above goal.

Conclusions:
Modest blood pressure interventions population-wide provide an opportunity to substantially reduce the burden of incident CKD. Among the high-risk population, lowering the threshold for blood pressure treatment to JNC 7’s treatment goal could increase the impact of high-risk strategies on CKD prevention when compared to JNC 8’s treatment goal.
Abstract 011: Retinal Signs Are Associated With Increased 20-Year Dementia Risk in the Atherosclerosis Risk in Communities Study
Authors: Deal Jennifer A , Sharrett A. Richey , Albert Marilyn , Bandeen-Roche Karen , Burgard Sheila , Davis Sonia , Gottesman Rebecca F , Knopman David , Mosley Thomas , Klein Barbara , Klein Robert
Published: July 2021

Introduction:
The microvascular contribution to dementia may be under-recognized because of the inability to visualize the brain microvasculature in vivo. Although the easily-imaged retinal vasculature may be a surrogate measure for that in the brain, large prospective studies of the relationship between retinal vascular signs and dementia are scarce.

Hypothesis:
Retinal signs are associated with greater subsequent risk of all-cause dementia and etiologic subtype over 20 years in 12482 men and women (mean age of 60 years when retinal signs were measured, 22% African American).

Methods:
Retinal signs were measured using fundus photography (1993-1995). Presence and etiology of dementia and mild cognitive impairment (MCI) were adjudicated using data collected in 2011-13, including a complete neuropsychological battery and brain magnetic resonance imaging (subset of participants). For participants not attending the 2011-13 visit, dementia cases were identified using the Telephone Interview for Cognitive Status–Modified or informant interview, or by hospitalization or death certificate code. Multivariable-adjusted Cox proportional hazards models and logistic regression were used to quantify the relationship of retinal signs with dementia risk and with etiologic subtype, respectively.

Results:
During a mean 16 years of follow-up, 1259 (10%) participants developed dementia. Moderate or severe (vs. no) retinopathy (hazard ratio [HR], 1.86; 95% CI: 1.36, 2.55) and generalized arteriolar narrowing, measured as the central retinal arteriolar equivalent (CRAE, narrowest quartile vs. widest three quartiles), (HR, 1.26; 95% CI: 1.09, 1.45) were associated with all-cause dementia. Results did not differ by diabetes, race or
APOE
ε4 genotype. Retinopathy was associated with cerebrovascular-related dementia and MCI (odds ratio, 2.66; 95% CI: 1.30, 5.42).

Conclusions:
Retinal photography captures small vascular signs in the eye that are related to increased dementia risk. Emerging techniques, such as optical coherence tomography angiography, may have the sensitivity to provide surrogate indices of microvascular lesions relevant to dementia in older adults.
Abstract 013: A Model for Stroke Prediction Using Claims Data in a Contemporary Cohort of Patients With Atrial Fibrillation Receiving Oral Anticoagulation
Authors: Claxton J'Neka S , MacLehose Richard F , Lutsey Pamela L , Norby Faye L , Chen Lin Y , O'Neal Wesley T , Chamberlain Alanna M , Bengtson Lindsay G , Alonso Alvaro
Published: July 2021

Background:
Oral anticoagulants (OACs) are recommended for AF patients for the prevention of thromboembolic events, including stroke. Stroke risk stratification scores (e.g., CHA
2
DS
2
-VASc) are used to tailor therapeutic recommendations for patients in different risk groups. However, these were derived before the advent of direct OACs. At present, there is no tool that estimates a patient’s stroke risk, given their individual characteristics, by type of OAC.

Methods:
We used healthcare utilization data from two independent US databases (MarketScan and Optum) to construct and validate a predictive model of ischemic stroke in patients with AF initiating OACs. Patients with non-valvular AF initiating OACs were identified from the MarketScan data for years 2007-2015. Using bootstrapping methods and backward selection of 44 candidate variables, we developed a model which selected variables predicting stroke. The final model was validated in patients with non-valvular AF in the Optum Clinformatics database in the period 2009-2015.

Results:
Among 135,523 patients with AF initiating OAC in the MarketScan dataset, 2,028 experienced an ischemic stroke after anticoagulant initiation. The stepwise model identified 15 variables (including type of OAC) associated with ischemic stroke (Table). The discrimination (c-statistic) of the model was adequate [0.68, 95% confidence interval (CI) 0.66-0.70], showing excellent calibration (χ
2
= 7.7 p=0.57). The model was then applied to the 84,549 AF patients in the Optum data set (1408 stroke events). The model showed similar discrimination (c-statistic 0.67, 95%CI 0.65-0.70) and calibration (χ
2
= 12.8 p=0.17). However, previously-developed predicted models had similar discriminative ability (CHA
2
DS
2
-VASc 0.67, 95%CI 0.65-0.68; ATRIA 0.67, 95%CI 0.65-0.68)

Conclusion:
A novel model using extensive administrative healthcare data for the identification of patients at higher risk of ischemic stroke by type of anticoagulant did not perform better than established simple models.