bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 9971: Comparison of Stents Coated with Antibody against CD34 versus Vascular Endothelial-Cadherin: Anti-VE-Cadherin-Antibody-Coated Stents are Better In Rapid Endothelialization and Reduction of Neointimal Formation
Authors: Lee Joo Myung , Choe WonSeok , Seo Won-Woo , Lim Woo-Hyun , Kang Chan-Koo , Kyeong San , Cho Hyun-Ju , Kim Baek-Kyung , Kim Young-Chan , Hur Jin , Yang Han-Mo , Park Kyung Woo , Cho Hyun-Jai , Lee Yoon-Sik , Kim Hyo-Soo
Published: April 2024

Background
Vascular endothelial-cadherin is exclusively expressed on the late endothelial progenitor cells. We evaluated whether anti-VE-cadherin antibody-coated stents might accelerate endothelial recovery and reduce neointimal formation more than anti-CD34 antibody-coated stents through the superior ability to capture the late EPC.

Methods
The BMS were coated with anti-VE-cadherin antibodies or anti-CD34 antibodies under the same condition. In vitro, the ability to capture EPC and specific cell capturing ability was evaluated. In vivo, re-endothelialization of stent in the rabbit iliac arteries was assessed by serial scanning electron microscopy. At 42 days, the area and proliferating activity of the neointima was compared between two stents.

Results
VE-cad stents showed higher number of adhering EPC (823.6 ± 182.2 versus 379.2 ± 137.2 cells/HPF, p<0.001). VE-cad stents also demonstrated better specific capturing of cells with endothelial lineage markers than CD34 stents did in flow cytometric analysis. VE-cad stents showed more effective re-endothelialization after 3 days in vivo. At 42 days, VE-cad stents demonstrated significantly smaller neointima area (0.92 ± 0.38 versus 1.24 ± 0.41 mm
2
, p=0.002) and significantly lower PCNA positive cells in neointima (1684.8 ± 658.8/mm
2
versus 2681.7 ± 375.1/mm
2
, p=0.008), compared with CD34 stents.

Conclusions
VE-cad stents captured EPC and endothelial cells more selectively in vitro, accelerated re-endothelialization over stents, and reduced neointimal formation in vivo, compared with CD34 stents. Targeting the VE-cadherin could be more reasonable strategy in developing the next generation pro-healing stents.
Abstract 17985: Deletion of Tissue Factor Pathway Inhibitor in Zebrafish Leads to Enhanced Thrombosis, Atherosclerosis, and Myocardial Infarction Injury
Authors: Hoffman Scott J , Clark Karl J , Poshusta Tanya L , Ekker Stephen C , Simari Robert D
Published: April 2024

Background:
The extent to which tissue factor pathway inhibitor (TFPI) may regulate the extrinsic clotting cascade, atherogenesis, and MI is uncertain. Reverse genetic studies in the mouse, including deletion of the TFPI Kunitz-1 (K1) domain, have been hindered by intrauterine lethality. We sought to determine the role of TFPI in an alternative animal model, by knocking out the zebrafish ortholog
tfpia
.

Methods and results:
High-efficiency transcription activator-like effector nucleases (TALENs), targeting the 5’ region of
tfpia,
were microinjected into 1-cell zebrafish embryos. Sequence analysis of genomic DNA derived from adult caudal fin tissue revealed indels causing a frameshift mutation and premature stop codon prior to K1. Somatic mutants were outcrossed to WT fish, and the embryos were screened for germline mutations. Founders (F
1
) were raised and incrossed to produce embryos (F
2
), including approximately 25% with the desired biallelic null mutation (
tfpia
-/-
) that were physically and developmentally indistinguishable, but functionally disparate from heterozygous (
tfpia
+/-
) or WT (
tfpia
+/+
) siblings. At 6 days post-fertilization (dpf), F
2
tfpia
-/-
larvae exhibited a reduction in time to occlusion of the dorsal aorta after exposure to ferric chloride, which was more significant in 6-dpf F
3
tfpia
-/-
larvae (generated by incrossing F
2
tfpia
-/-
adults) lacking a possible maternal effect. Furthermore, F
2
tfpia
-/-
fish had
in vivo
evidence of increased fatty streaking as late larvae, after receiving a high cholesterol diet, and enhanced cardiac injury as adults, 4 days after cryoinjury-induced MI.

Conclusions:
Deletion of
tfpia
does not significantly effect zebrafish development, but leads to hypercoagulability in early larvae, enhanced atherogenesis in late larvae, and increased injury related to MI in adults, indicating a fundamental role for TFPI in the pathogenesis of cardiovascular disease.
Abstract 18000: The Role of X-box Binding Protein 1 Splicing in Smooth Muscle Cell Proliferation and Neointima Formation
Authors: Zeng Lingfang , Li Yi , Hu Yanhua , Xu Qingbo
Published: April 2024

Background:
Smooth muscle cell (SMC) proliferation plays an important role in neointima formation in response to vascular injury. However, the underlying mechanism is still not well understood. It has been well documented that endoplasmic reticulum (ER) stress plays a provoking role in cardiovascular disease including neointima formation. As one of the key transducer in ER stress response, the X-box binding protein 1 (XBP1) has been demonstrated to contribute to endothelial cell proliferation, autophagic response and apoptosis, but less is known about its role in SMC growth.

Methods and Results:
In this study, we intend to study the role of XBP1 in SMC proliferation and its contribution to neointima formation in response to vascular injury. Quantitative RT-PCR and immunohistological staining analysis revealed that XBP1 splicing was up-regulated in the arterial vasculature in aged ApoE deficient mice and in response to vascular injury in wild type mice with elevated XBP1 protein in the neointima. Platelet derived growth factor (PDGF) induced XBP1 splicing via the interaction between PDGF receptor and inositol requiring enzyme 1 alpha (IRE1α). Transient over-expression of the spliced XBP1 (XBP1s) increased SMC proliferation, while knockdown of XBP1 or IRE1α abolished PDGF-induced SMC proliferation. XBP1s down-regulated calponin H1 gene expression at mRNA and protein levels, which might be through the down-regulation of TGFβ3 signalling. Reconstitution of calponin H1 via adenoviral transfer could ablate XBP1s-induced SMC proliferation. Addition of exogenous TGFβ3 abolished XBP1s-induced calponin H1 suppression and SMC proliferation. High levels of TGFβ3 and calponin H1 were detected in SMCs isolated from SM22-Cre/XBP1
loxP
mice. These SMCs showed retardation in proliferation as compared to SMCs from wild type litters. Importantly, in the femoral artery injury model, XBP1 deficiency in SMCs prevented the neointima formation.

CONCLUSION:
XBP1 splicing plays an important role in SMC proliferation via regulating calponin H1 expression. Targeting XBP1 splicing in SMC may provide a novel therapeutic strategy to intervene neointima formation.
Abstract 18006: Nuclear Calcineurin is a Sensor for Detecting Ca2+ Release From the Nuclear Envelope via InsP3R
Authors: Czolbe Martin , Muehlfelder Melanie , Nordbeck Peter , Olivares Silvana , Seidlmayer Lea , Williams Tatjana , Ritter Oliver
Published: April 2024

Background:
Recent evidence demonstrates that not only NFAT, but also calcineurin (CN) is translocated to the nucleus upon hypertrophic stimulation. It was also shown that calpain-mediated degradation caused a constitutive active CN. We hypothesised 1) that nuclear CN is an intranuclear Ca2+ sensor, 2) that the nucleus in cardiac myocytes is a Ca2+ microdomain largely independent of cytosolic Ca2+ alterations and that 3) inhibition of nuclear translocation of CN is a therapeutic strategy to prevent hypertrophy.

Methods:
Employing a transgene mouse model with conditional calpastatin overexpression (resulting in calpain inhibition), different adenoviral CN mutants and confocal microscopy in isolated adult cardiac myocytes we investigated CN translocation and nuclear Ca2+ transients. Assessment of cardiac function in transgenic animals was performed by MRI.

Results:
We could demonstrate that chronic Ang II stimulation of mice caused calpain-mediated degradation of CN resulting in a constitutive active CN with nuclear translocation. The constitutive active CN in the nucleus escaped degradation by the UPS and sustained an ongoing hypertrophic response, even after removal of Ang II. Transgenic inhibition of calpain by calpastatin overexpression prevented proteolysis of CN and allowed for relocation of CN from the nucleus back to the cytosol and regression of hypertrophy after removal of Ang II. Inhibition of the interaction between CN and the transport protein importin ß1 by an inhibitory peptide prevented nuclear translocation of activated CN. The synthetic peptide prevented myocardial hypertrophy in vivo. We were able to demonstrate that Ang II increases nuclear Ca2+ transients via nuclear InsP3 receptors. We also showed that Ca2+ levels are constantly elevated during diastole (up to 0.2 μM) in Ang II stimulated cardiac myocytes and that CN is able to act as nuclear Ca2+ sensor detecting this local Ca2+ release from the nuclear envelope via InsP3R. Nuclear CN mutants that are defective for Ca2+ activation failed to activate NFAT dependent transcription.

Conclusion:
These results provide an explanation how Ca2+ and CN can regulate transcription in cardiac myocytes in response to neurohumoral signals apart from Ca2+ changes in contraction regulation.
Abstract 18029: Copper Transporter ATP7A Protects Against Endothelial Barrier Dysfunction in Ischemic Injury in Diabetes
Authors: Varadarajan Sudhahar , Chen Gin-Fu , Urao Norifumi , McKinney Ronal D , Ushio-Fukai Masuko , Fukai Tohru
Published: April 2024

Endothelial barrier dysfunction is the major vascular complications in inflammatory diseases such as diabetes mellitus (DM). Copper (Cu), an essential micronutrient, plays an important role in physiological repair processes. Since excess Cu has been implicated in various pathophysiologies such as DM, intracellular Cu levels are tightly controlled by Cu exporter ATP7A. In this study, we investigated a role of ATP7A in DM-induced endothelial barrier dysfunction using ischemic limb injury model. Here we show that ATP7A protein expression is markedly upregulated (>2 folds) in ischemic injured tissue, which is significantly decreased in streptozotocin (STZ)-induced type1 DM mice. ATP7A dysfunctional mutant mice or DM mice show increased vascular permeability (assessed by Miles assay), excess macrophage infiltration, and tissue damage in ischemic tissue vs. control mice. In endothelial cells (ECs), ATP7A knockdown with siRNA or ECs derived from DM mice increases EC permeability (132%) as measured by transendothelial electric resistance in a Cu-dependent manner. This is due to decreased protein expression of VE-Cadherin (VE-Cad; 40% decrease), but not beta-catenin, thereby disrupting adherence junctions as visualized by beta-catenin staining. Mechanistically, ATP7A siRNA induces microRNA (miR)-125b (1.8 fold), which reduces VE-Cad protein, in a Cu-dependent manner. Of note, anti-miR125b rescues siATP7A-induced decrease in VE-Cad protein as well as increased EC permeability. ECs or ischemic tissues from DM mice show decreased ATP7A or VE-Cad protein expression and increased miR125b expression (P<0.05). Moreover, ATP7A-depleted ECs exhibit disassembly of actin as visualized by phalloidin through activating Rac1 (1.4 fold), which is inhibited by Cu chelator TTM. Functionally, DM-induced vascular leakage and tissue damage in ischemic limbs is rescued in ATP7A overexpressing transgenic mice treated with STZ. In summary, Cu exporter ATP7A protects against endothelial barrier dysfunction in DM by suppressing miR-125b that downregulates VE-Cad as well as by inhibiting Rac1-mediated actin disassembly. Thus, ATP7A is a potential therapeutic target for promoting tissue repair in diabetic inflammatory ischemic disease.
Abstract 18046: miR-21 is a Biomarker for Fibrosis and the Progression to Right Ventricular Systolic Failure in a Model of Pulmonary Volume and Pressure Overload
Authors: Reddy Sushma , Hu Dong-Qing , Zhao Mingming , Blay Eddie , Fajardo Giovanni , Bernstein Daniel
Published: April 2024

Introduction:
Severe pulmonary insufficiency (PI) in combination with moderate pulmonary stenosis (PS) is a common long-term complication after repair of congenital heart diseases such as tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We characterize the physiologic and molecular characteristics of the first murine model of combined RV volume and pressure overload (PI/PS).

Methods:
Physiologic data was compared between sham controls and PI/PS at 1 and 3 mos. Histopathology and gene, microRNA (miR) and protein expression were assessed in the RV free wall. Plasma miR expression was assessed in children with severe PI/moderate PS vs controls (n=4).

Results:
Data are presented as sham vs. PI/PS at 1 and 3 mos (*p<0.05). Mice developed diastolic heart failure at 1 mo progressing to systolic heart failure by 3 mos: restrictive RV filling (E/A ratio) (0.7±0.1 vs. 2.1±0.9 and 1.9±0.4*) and elevated RV end-diastolic pressure (2.7±0.3 vs. 7.8±2, and 8.5±2 mmHg*); followed by decreased RV outflow tract shortening (44±2 vs. 39±6 and 29±6%*) and exercise capacity (32±1.1 vs. 28±1.6 and 22±1.9 min*). RV fibrosis increased over time (0 vs. 4.0±2, 3.9±0.2%* sham vs 1 and 3 mos) along with pSMAD/total SMAD expression (0.2±0.1 vs. 0.4±0.1 and 0.6±0.1*), ANP expression (25±15 and 60±27* fold at 1 and 3 mos) and tissue miR-21 expression (2.7±0.3 and 2.9±0.6 fold). However, plasma miR-21 was upregulated with diastolic heart failure and switched to being downregulated with the development of systolic heart failure (2.6±1 and -1.8 ±0.2 fold). Finally, plasma miR-21 expression from children with severe PI/moderate PS at the time of pulmonary valve replacement was downregulated compared to controls (FC -3.6±1.2).

Conclusion:
We describe a novel murine model of chronic RV volume and pressure overload which recapitulates many aspects of the clinical disease. Gene and protein expression changes suggest enhanced miR-21 and TGF-β signaling as a mediator of RV fibrosis. miR-21 may serve as a novel biomarker of RV fibrosis, with a decline in expression heralding the need for valve replacement. This model provides investigators with a new tool for further evaluation of a form of RV failure unique to children with repaired congenital heart disease.
Abstract 18048: Early Termination of Cardiovascular Clinical Trials Registered in ClinicalTrials.gov: Where Do We Stand?
Authors: Pereira Sabrina B , Lopes Renato D , Carrion Maria Julia , Santucci Eliana V , Soares Rafael M , Abreu Matheus O , Laranjeira Ligia N , Ikeoka Dimas T , Zazula Ana , Moreira Frederico R , Cavalcanti Alexandre B , Mesquita Evandro T , Peterson Eric D , Califf Robert M , Berwanger Otavio ,   Methodological Evaluation of Clinical Trials (META) Study Group
Published: April 2024

Importance:
Early termination of clinical trials represents a challenge in clinical research, yet little is known about the frequency and reasons for it.

Objective:
We aimed to describe reasons for termination, and identify the major predictors of early termination due to low recruitment.Study Selection: We reviewed all cardiovascular clinical trials registered in ClinicalTrials.gov from February 29, 2000 to January 17, 2013 and assessed information about trials that were completed and those that were terminated early.Data Extraction and Synthesis: The dataset was downloaded in XML containing all cardiovascular studies registered. The dataset was exported into R software to extract the values. Logistic regression models were developed to identify independent predictors of early termination due to low recruitment.Main Outcome Measure: Studies classified as completed or terminated prematurely, and reasons for termination.

Results:
Overall,684 of 6279 trials included (10.9%) were terminated prematurely. The main reason for early termination was lower than expected recruitment rates (278 trials; 53.6%); 24.1% of trials had no clear justification for premature termination. When comparing trials that terminated early due to low recruitment with those that were completed, we found that studies funded by the National Institutes of Health/ United States federal agencies (odds ratio [OR] 0.35, 95% confidence interval [CI] 0.14-0.89), studies of behavior/diet intervention (OR 0.35, 95% CI 0.19-0.65), and single-arm design studies (OR 0.57, 95% CI 0.42-0.78) were associated with a lower risk of early termination. University/hospital (OR 1.52, 95% CI 1.10-2.10) and mixed-source funded studies (OR 2.14, 95% CI 1.52-3.01) were associated with a higher likelihood of early termination due to lower than expected recruitment rates.

Conclusions and Relevance:
Early termination of interventional cardiovascular trials is common and most frequently due to low recruitment. Funding source, type of intervention, and study design were factors associated with early termination due to low recruitment and might be good targets for the improvement of clinical trial conduct.
Abstract 18067: Phosphodiesterase 4B Controls a Subsarcolemmal Pool of Cyclic AMP
Authors: Mika Delphine , Richter Wito , Conti Marco
Published: April 2024

Rationale:
Sympathetic regulation of the heart is mediated via β1- and β2-adrenergic receptors (βARs). Both receptors signal through cAMP, but produce distinct or even opposing effects on cardiac function. Localized or compartmentalized cAMP is thought to be the basis for these differential effects. Cyclic nucleotide phosphodiesterases (PDEs), the enzymes that degrade and inactivate cAMP, may contribute to compartmentalization and βAR signaling specificity.

Objective:
To elucidate the role of the cardiac PDE4B in βAR signaling.

Methods and Results:
Cyclic AMP accumulation was measured with FRET-based cAMP sensors in cytosolic and sarcolemmal compartments of cardiomyocytes from Wild Type and PDE4BKO mice. Ablation of PDE4B alters the cAMP transient induced by βAR stimulation at the sarcolemma but not in the cytosol. The effect of PDE4B ablation is further restricted to β1AR-induced cAMP transients, whereas β2AR or E prostanoid receptor (EPR) responses are not affected. In PDE4BKO cells, PKA-phosphorylation of proteins in the sarcolemmal compartment, including the vasodilator-stimulated phosphoprotein, the L-type Ca2+ channel (LTCC), the ryanodine receptor (RyR2) is increased. Conversely, phosphorylations of proteins distant from the cell membrane, including phospholamban or contractile proteins are not affected. β1AR but not β2AR ligation causes PKA-dependent activation of PDE4B. PKA inhibition produces a significant increase in subsarcolemmal cAMP in Wild Type cardiomyocytes, but has only a limited effect in PDE4BKO myocytes, confirming that this feedback regulation of PDE4B shapes the cAMP transient at the sarcolemma. Consistent with the augmented phosphorylation of LTCC and RyR2, contraction rate in PDE4BKO myocytes in response to βAR stimulation is increased compared to Wild Type.

Conclusions:
PDE4B mediates a critical PKA-dependent feedback mechanism that controls β1AR-, but not β2AR- or EPR-induced cAMP signals. This regulation functions in a restricted subsarcolemmal compartment containing LTCC and RYR2.
Abstract 18084: Diabetes Promotes Tissue Nitric Oxide (NO) Insufficiency in Critical Limb Ischemia Patients
Authors: Polhemus David , Goodchild Traci , Lefer David J , Brewster Luke P
Published: April 2024

Background:
Diabetic patients are 5 times more likely than non-diabetics to develop critical limb ischemia (CLI). The pathogenesis of CLI in diabetic patients remains poorly understood and at present there is a paucity of effective therapies to treat this devastating disease. Nitrite (NO2) and nitrosothiols (RSNO) have recently emerged as important storage forms of nitric oxide (NO) that modulate vascular reactivity and signaling. The purpose of this study was to investigate tissue NO bioavailability in muscle biopsies obtained from non-diabetic and diabetic (Db) patients following leg amputation.

Methods:
Gastrocnemius and tibialis anterior tissue was attained post-amputation from human non-diabetic patients with CLI (n=12) and diabetic patients with CLI (n=8). Nitrite concentrations were determined by ion chromatography methods. RSNO and NO-Heme levels were measured by chemiluminescence detection.

Results:
The CLI + Db group displayed reduced skeletal muscle (89.9 vs. 55.5 nM, p < 0.05) nitrite levels compared to the CLI group without Db. Nitrosothiol (21.2 vs. 10.52 nM, p < 0.05) concentrations and NO-Heme (27.61 vs. 13.0 nM, p < 0.05) levels were also significantly attenuated in the CLI + Db group.

Conclusion:
These data clearly indicate significant reductions in NO bioavailability (nitrite, RSNO, and NO-heme) in diabetics with CLI. Future studies will evaluate the cellular mechanisms responsible for reduced NO levels in diabetic patients with CLI. Nitric oxide based therapeutics including sodium nitrite may be suitable to treat diabetic patients with CLI to attenuate the progression of this disease.
Abstract 18087: Docosahexaenoic Acid Complexed to Albumin as a Promising Neuroprotectant in Brain Ischemia
Authors: Belayev Ludmila , Khoutorova Larissa , Obenaus Andre , Eady Tiffany N , Bazan Nicolas G
Published: April 2024

Background:
Recently we have shown that docosahexaenoic acid (DHA), a component of fish oil, complexed to human serum albumin (Alb) is highly neuroprotective after experimental stroke in young rats. The purpose of this study was to determine whether treatment with DHA-Alb complex would be protective in aged rats after focal cerebral ischemia.

Methods and Results:
Isoflurane/nitrous oxide-anesthetized normothermic (brain temperature 36-36.5
o
C) Sprague-Dawley aged rats (18-months old) received 2 h middle cerebral artery occlusion (MCAo) by poly-L-lysine-coated intraluminal suture. The neurological status was evaluated during occlusion (60 min) and on days 1, 2, 3 and 7 after MCAo; a grading scale of 0-12 was employed (normal score=0, maximal deficit=12). DHA (5mg/kg), Alb (0.63g/kg), DHA-Alb (5mg/kg+0.63g/kg) or saline was administered i.v. 3 h after onset of stroke (n=8-10 per group).
Ex vivo
T2-weighted imaging (T2WI) of the brains was conducted on an 11.7T MRI on day 7 and 3D reconstructions were generated. Infarct volumes and number of GFAP (reactive astrocytes), ED-1 (activated microglia/microphages), NeuN (neurons)-positive cells and SMI-71 (positive vessels) were counted in the cortex and striatum at the level of the central lesion. Physiological variables were entirely comparable between groups. Animals treated with DHA-Alb showed significantly improved neurological scores compared to vehicle rats; 33% improvement on day 1; 39% on day 2; 41% on day 3; and 45% on day 7. Total and cortical lesion volumes computed from T2WI were significantly reduced by DHA-Alb treatment (62 and 69%, respectively). In addition, treatment with DHA-Alb reduced cortical and total brain infarction while promoting cell survival.

Conclusions:
We conclude that DHA-Alb therapy is highly neuroprotective in aged rats following focal cerebral ischemia and has potential for the effective treatment of ischemic stroke in aged individuals.
Abstract 18094: Multimorbidity and 30-Day All-Cause Readmission Among Hospitalized Medicare Beneficiaries With Heart Failure
Authors: Parvataneni Sridivya , Inampudi Chakradhari , Patel Kanan , Ritchie Christine , Fonarow Gregg C , Brown Cynthia J , Morgan Charity J , Prabhu Sumanth D , Aronow Wilbert S , Deedwania Prakash , Butler Javed , Allman Richard M , Ahmed Ali
Published: April 2024

Background:
According to the Centers for Medicare and Medicaid Services (CMS), Medicare beneficiaries with ≥6 chronic conditions have the highest (25%) 30-day all-cause readmission rate (Chronic Conditions among Medicare Beneficiaries, Chartbook, 2012). Heart failure (HF) is the only single chronic condition with similarly high 30-day all-cause readmission rates (PMID: 19339721). In the current analysis, we examined the additional impact of comorbidity burden on 30-day all-cause readmission in patients with HF.

Methods:
We analyzed data from 8049 Medicare beneficiaries discharged alive from 106 U.S. hospitals during 1998-2001. We identified 14 chronic medical conditions used by the CMS (HF being index condition in the current analysis) and categorized patients into 0 (n=123), 1 (n=533), 2 (1395), 3 (n=2016), 4 (n=1986) and ≥5 (n=1996) comorbidities. Because the incidence of 30-day all-cause readmission was similar for those with 0-3 morbidities (20%, 16%, 18% and 18%, respectively; overall, 18%), we combined these 4 groups and used them as reference to estimate age-sex-race-adjusted hazard ratios (HR) for those with 4 and ≥5 comorbidities using Cox regression models.

Results:
Patients had a mean age of 76 (±11) years, 58% were women, and 25% were African American. Age-sex-race-adjusted associations of 4 and ≥5 comorbidities with outcomes are displayed in the
Table
below.

Conclusions:
For hospitalized older patients with HF, the risk of 30-day all-cause readmission was comparable for those with 0-3 comorbidities, which progressively increased for those with 4 and ≥5 comorbidities. However, comorbidity burden seems to have a modest association with 30-day all-cause mortality. These findings suggest that the CMS’s chronic condition list may be used to identify hospitalized older HF patients at higher risk for 30-day all-cause readmission, a current target of health care reform which could reduce costs for Medicare.

_
Abstract 18101: Three-Dimensional Echocardiography Identify Mechanisms of Early Post Operative Valve Failure in Pediatric and Congenital Heart Disease
Authors: Zahari Norazah , Colen Timothy , Suntratonpipat Somjate , Al-Habdan Mohammed , Ross David , Al-Aklabi Mohammad , Rebeyka Ivan M , Smallhorn Jeffrey F , Khoo Nee S
Published: April 2024

Background:
Three-dimensional echocardiography (3DE) is an accurate and informative imaging modality routinely used in pre-operative assessment for surgical planning. There is however little information on 3DE role in early post-operative valve failure assessment. This is a report on our 5 years experience of 3DE in early post-operative mitral/left atrioventricular valve (MV/LAVV) failure assessment, its impact on our understanding of its mechanism and the clinical decision for returning to the operating theatre for re-repair.

Methods and results:
We retrospectively reviewed all patients chart and echo with MV/LAVV surgery between 2008 and 2012, excluding primary repair of atrioventricular septal defect (AVSD) and primary valve replacement. Early valve failure (EVF) is defined as moderate or greater MV/LAVV regurgitation within 30 days post repair. There were 132 MV/LAVV surgeries consisting of repaired complete AVSD (n=85), congenital MV abnormality (n= 17) and primum AVSD (n= 16). Pre operative moderate or greater regurgitation was present in 55 (42%) and post op EVF in 33 patients (25%). 3DE were performed in 22 (67%) of 33 EVF with 8 patients returning to the operating room for re-repair due to poor clinical progress in intensive care unit. Six of 8 re-repair were infants. 3DE accurately identified the mechanism of regurgitation such as suture dehiscence at base of cleft, leaflet tears and patch failure (see Figure). Four of 8 patients MV/LAVV regurgitation improved to mild or less regurgitation at follow-up (median 2 months), 3 remained unchanged and 1 subsequently died from intractable heart failure despite MV/LAVV regurgitation improving from severe to moderate.

Conclusion:
Although patient returning for re-repair of EVF were mainly driven by poor clinical progress in intensive care. 3DE accurately identified the mechanism of early post-operative valve failure thus facilitating surgical planning and decision for re-repair.
Abstract 18127: Gene Expression Changes Associated With β-Blocker Reverse Remodeling in the Failing Human Heart Constitute a β1-Adrenergic Receptor Gene Regulatory Network
Authors: Epperson L. E , Kao David P , Minobe Wayne , Gilbert Edward M , Lowes Brian D , Bristow Michael R
Published: April 2024

Background:
When β-blocking agents produce reverse remodeling on nonischemic dilated cardiomyopathies (NDCMs) they effect a partial reversal of heart-failure associated changes in expression of constituents of the classic fetal-adult contractile protein (CP)/natriuretic peptide (NP)/SR Ca2+ ATPase (SERCA2a) gene "program". We have also reported that the DCM abnormalities in CPs, SERCA2a and NPs are associated with evidence of hypothyroidism at the thyroid hormone receptor (THR)-α level.

Methods and results:
We treated 47 NDCM patients (mean baseline LVEFs 24+9%, RVEFs 27+9%) with β-blockers (metoprolol CR/XL, metoprolol + doxazosin, or carvedilol in a randomized allocation) for 18 months. A total of 37 patients had reverse remodeling responses. mRNA expression from RV septal biopsies at baseline, 3 and 12 months of treatment was assessed by quantitative PCR for 50 prespecified genes, as well as using microarrays that included sequences for 21,700 human genes (Affymetrix HGU133 plus 2.0). The 50 prespecified genes were selected for having fetal or adult expression characteristics, being THR or β1 adrenergic receptor (AR) responsive, or for encoding Gq-coupled, metabolic or cytokine proteins. Using last-observation-carried-forward and non-parametric statistical analysis, 21 genes changed expression in the 37 patients who had reverse remodeling responses compared to the 10 patients who did not. All 21 reverse remodeling-associated genes have been previously described as being regulated by β1-AR signaling. Seventeen (81%) of the 21 changed mRNAs had a previously described fetal-adult pattern, and 72% were THR responsive. Of the changed β1-AR responsive genes, 13/21 were also statistically significant by microarray analysis, with all 21 mRNAs changing in the same direction on the microarray as in the qPCR results.

Conclusion:
Myocardial gene expression changes associated with β-blocker reverse remodeling of human NDCMs are most consistent with a β1 adrenergic receptor gene regulatory network. The transcription factors and/or miRs involved in this network remain to be identified.
Abstract 18129: Sex-Based Comparison of Angina Severity, Extent of Inducible Ischemia, and Burden of Angiographic Coronary Disease: A Post Hoc Analysis of the COURAGE Trial
Authors: Acharjee Subroto , Sidhu Mandeep S , Hartigan Pamela M , Teo Koon K , Maron David J , Sedlis Stephen P , Mancini G.B. John , Chaitman Bernard R , Spertus John A , Weintraub William S , Boden William E
Published: April 2024

Background:
While sex-based differences in anginal symptoms are well-described, it is unclear whether similar differences exist in the extent of inducible ischemia and angiographic findings between men and women with stable ischemic heart disease. We examined the interrelationship of angina severity, objective measures of ischemia (by myocardial perfusion imaging [MPI]), and the burden of angiographic coronary artery disease (CAD) in both men and women participants in the COURAGE trial.

Methods:
At baseline, 2,279 patients underwent coronary angiography and were divided into subgroups based on the number of diseased vessels and a myocardial jeopardy score to assess the extent/magnitude of inducible ischemia. Men and women were further stratified by Canadian Cardiology Society (CCS) angina class and were compared across measures of ischemia and anatomy. The 625 patients who underwent baseline stress MPI were also stratified by both angina severity and extent of angiographic CAD. Odds ratios for angina were calculated and compared by sex, after adjusting for potential confounders.

Results:
In the unadjusted analysis, as compared with men, women had a similar overall prevalence of angina (86.4% vs. 87.8%, p = 0.47) and mean percent ischemic myocardium (7.9% vs. 7.7%, P = 0.84), but a lower prevalence of 3-vessel CAD (14.5% vs. 24.5%, P= 0.001) and mean jeopardy score (2.3% vs. 2.5%, P = 0.08), despite exhibiting a greater proportion of CCS II-III angina (64.5% vs. 56.5%, P = 0.006); see Figure 1. After multivariable adjustment, the significantly higher prevalence of CCS Class II-III angina in women persisted.

Conclusion:
For any given severity of angiographic CAD or extent of myocardial ischemia, women had more moderate-severe (CCS Class II-III) angina than did men. However, this difference was more pronounced in subgroups of patients with more extensive angiographic CAD or severe ischemia by MPI, which likely reflects a greater atherosclerotic burden.
Abstract 18133: Between- and Within-Person Changes in Weight and Cardiorespiratory Fitness and the Effect on Blood Pressure and Lipids in Men and Women From the Cooper Center Longitudinal Study
Authors: Finley Carrie E , Leonard David S , Barlow Carolyn E , Haskell William L
Published: April 2024

Introduction:
Cardiovascular disease (CVD) is the leading cause of death in the U.S. Controlling risk factors such as hypertension and dyslipidemia by maintaining a healthy weight and achieving an adequate level of cardiorespiratory fitness (CRF) could result in improvements in cardiovascular health. The Cooper Center Longitudinal Study is the most extensive resource available for evaluating the simultaneous effects of changes in weight and CRF on CVD risk factors.

Objective:
The purpose of this study was to evaluate the within-person relationships between body weight, CRF, and CVD risk factors, while controlling for the corresponding between-person relationships. We hypothesized that increases in weight and decreases in CRF over a ten-year time period would result in detrimental effects on blood pressure and lipids, and vice-versa.

Methods:
The study sample consisted of 4,439 men and 651 women who had at least 5 preventive medical examinations during any ten year period from 1977 to 2006. The examination included a maximal exercise test, anthropometric and clinical measures, and a medical history questionnaire. Linear mixed-effects regression was used to model the cardiovascular risk factors over time, providing estimates of between- and within-person effects.

Results:
Aging alone did not significantly predict changes in CVD risk factors in women or men after adjustment for covariates including CRF and weight, with the exception of total and LDL cholesterol in men. Increases in body weight were associated with increases in systolic and diastolic blood pressure, total cholesterol, LDL, and triglycerides and decreases in HDL in women and men. The largest effect of weight gain for women and men was seen in triglycerides, with a 2.29 mg/dL and 3.57 mg/dL increase per pound of weight gained per year, respectively (
P
< 0.001). Increases in CRF were associated with improvements in diastolic blood pressure [-0.39 mmHg (women); -0.10 mmHg (men)] and HDL [0.35 mg/dL (women); 0.63 mg/dL (men)] over time and in triglycerides (-2.26 mg/dL) in men only (
P
< 0.05 for all).

Conclusion:
Changes in body weight over a ten year period predicted changes in all CVD risk factors examined in women and men; whereas changes in CRF predicted changes in diastolic blood pressure and HDL.
Abstract 18136: Mechanical Circulatory Support for Failing Systemic Right Ventricle - A Viable Bridging Strategy to Transplant?
Authors: Peng Ed , O’Sullivan John , Griselli Massimo , Crossland David , Chaudhari Milind , Wrightson Neil , Butt Tanveer , Parry Gareth , MacGowan Guy , Schueler Stephan , Hasan Asif
Published: April 2024

BACKGROUND:
The morphological right ventricle in the systemic position is associated with late failure and cardiac transplantation becomes the only treatment option. In the face of declining heart donor, the role of left ventricular assist device (VAD) as a bridge to transplant is well established. However, there is only scarce experience of supporting failing systemic right ventricle (RV).

METHODS:
Between 1989 and 2013, a total of 21 adult patients (age 18 years and above) had heart transplant in our institution for systemic RV failure. Since our inception case to support failing systemic RV mechanically in 2009, a total of six adult patients (5 males, mean age 36 years; 4 post atrial switch, 2 ccTGA) had been supported (5 Heartware and 1 Berlin Heart). Concomitant systemic atrioventricular surgery was required in two patients. Indications for systemic RV-VAD were (i) bridge to transplant (n=2) (group BTT) and (ii) bridge to further decision in the presence of high transpulmonary gradient and/or high PRA (n=4) (group BTD).

RESULTS:
Early mortality (< 30 days) was 16.7% (n=1). One further patient died in-hospital following non-cardiac procedure (day 62). Overall, median ICU stay was 6 days (range 5-8 days). Four patients were discharged home: three patients reported significant improvement in functional capacity and serial TPGs assessment showed significant improvement. In group BTT, 1 was transplanted (at day 313 post-VAD). In group BTD, 1 patient was transplanted (day 685), one has on-going support (currently 375 days), and one died (day 232, sepsis and multi-organ failure). Three patients (50%) had cerebrovascular events (3, 4, 15 months post-VAD) with satisfactory recovery and one had recurrent bleeding episodes. One patient required further surgery (aortic valve replacement and device replacement due to thrombosis). Survival at transplant was 100% for those with VAD (n=2) (vs 89.5% for those without VAD support, n=17/19).

CONCLUSION:
The use of ventricular assist device to support failing systemic RV is a viable strategy to bridge for transplant or further assessment. Neurological event, albeit with satisfactory recovery, remains a significant morbidity.
Abstract 18146: Increased Physical Activity is Associated With Lower Risk of Non Alcoholic Fatty Liver Disease Across Spectrum of Cardiometabolic Risk
Authors: Oni Ebenezer T , Aneni Ehimen , Karim Adil , Mazaik Wasim , Feldman Theodore , Blaha Michael , Martin Seth S , Agatston Arthur A , Blumenthal Roger S , Conceiçao Raquel D , Meneghelo Romeu S , Carvalho Jose A , Santos Raul D , Nasir Khurram
Published: April 2024

BACKGROUND:
Non-alcoholic fatty liver disease (NAFLD) has been linked with increased cardiovascular risk. Its prevalence is associated with increase in obesity and insulin resistance. Although physical activity (PA) and life style modification are often recommended to treat NAFLD, the benefit across metabolic risk spectrum is unclear. We aimed to evaluate the relationship of PA and NAFLD independent of the metabolic syndrome (MS).

METHODS:
We evaluated 5,743 healthy Brazilian subjects (43±10 years, 79% males) without clinical coronary heart disease between November 2008 and July 2010. NALFD was ultrasound diagnosed and PA was assessed using the International Physical Activity Questionnaire (IPAQ) scale. MS was classified with the IDF criteria. In hierarchical regression models, we evaluated for an independent association of NAFLD and physical activity (PA).

RESULTS:
The prevalence of NAFLD was 36% (n=2,075) and 1,152 (20%) had metabolic syndrome. NALFD was significantly higher in those with MS (74%) vs those without MS (26%), p<0.001. Overall 1,304 (23%) individuals were sedentary and 1,987(35%) had minimal activity. The prevalence of NALFD decreased significantly with increasing levels of PA reported (sed: 45%, minimally active: 38%, active= 30%, p<0.001). As shown in table below, after adjusting for confounding variables, higher activity levels was 16-31% less likely associated with NALFD. The benefit appeared to be extend to individuals with and without MS,

Conclusions:
PA presents a dose response association with hepatic steatosis independent of the MS. The benefits of PA is not only relevant in MS individuals but should also be emphasized in a non-MS population
Abstract 18147: Association of the First Occurrence of Atrial Fibrillation With Short-Term ICD Therapy and Heart Failure Exacerbation
Authors: Saltzman Heath E , Lindenfeld JoAnn , Jones Paul , Houle Vicki , Stivland Tim , Jiang Songtao , Kusmirek Slawomir L
Published: April 2024

Background:
Atrial fibrillation (AF) predicts inappropriate therapy and mortality in patients (pts) with implantable cardioverter defibrillators (ICDs). The short term effects of AF in pts with ICDs are not known. We sought to determine if AF burden affected 30 day morbidity as defined by heart failure (HF) exacerbations and ICD therapy.

Methods:
Pts enrolled in the LATITUDE home monitoring system were analyzed. Devices with greater than 1% AF during a 30-day period were included and divided into deciles based on the AF burden. The deciles were compared on number of ICD shocks, blood pressure and heart rate measures, and 6 HF symptom questions from the LATITUDE monitoring system. Symptom questions were scored as “-1” for improved, “0” for same, and “1” for worsened.

Results:
4258 pts were identified with an AF burden >1%. Of those, 3197 had heart failure observations recorded before and after the AF episode. Compared with before the 1st AF episode, in the month following, pts had a worsened activity level (
P
<0.001), systolic blood pressure (
P
<0.001), and heart rate variability (
P
=0.005). Pts also reported worsened dizziness (
P
<0.001), edema (
P
=0.006), exercise capacity (
P
=0.01), orthopnea (
P
<0.001), and more episodes of nocturnal dyspnea (
P
<0.001) The trend for nocturnal dyspnea and fatigue was significant across AF burden deciles (Figure). There was no difference in the mean number of shocks after the analyzed month of AF.

Conclusion:
Short term AF burden is predictive of worsened HF symptoms but not ICD shocks.
Abstract 18153: Gene-Smoking Interactions in CHD Risk - Analyses of the CARDIoGRAMplusC4D Data in 60,000 CHD Cases and 80,000 Controls
Authors: Saleheen Danish , Young Robin , Ferguson Jane , Ho Weankee , Zhao Wei , Rader Daniel J , Samani Nilesh , Danesh John , Reilly Muredach
Published: April 2024

Background:
Tobacco use is one of the most important avoidable causes of coronary heart disease (CHD). GWAS have discovered variants that lead separately to CHD and smoking behaviour; however no large scale studies exist that have investigated the interaction of sequence variants and tobacco use on CHD.

Objective:
To investigate gene-smoking interaction in CHD at known genetic loci related to CHD (n=45) and smoking (n=5) behavior.

Methods:
Studies participating in the CARDIoGRAMplusC4D consortium (n=37) with available genetic data (GWAS and/or CARDIOMETABOCHIP) and information on smoking exposure were invited to participate. For all genetic variants, each participating study was asked to provide effect estimates and standard errors in relation to CHD separately in current smokers, ever smokers and never smokers. Within each study, beta(s) were quantitatively compared between (i) current smokers vs. never smokers, and (ii) ever smokers vs. never smokers. Study specific interaction beta(s) and se(s) were calculated, which were pooled across using a fixed-effects meta-analysis. Interaction analyses were declared to be significant at a P-value of < 1.0x10-3 (Bonferroni correction for 50 tests).

Results:
Genetic data and information on smoking exposure was available on 60,919 CHD cases and 80,243 controls from 29 studies. Of the 45 CHD loci investigated, the reported CHD SNP at the ADAMTS7 locus had differential CHD association in non-smokers compared to ever smokers (P-value of interaction: 7.1 x 10-5). Multiple additional variants at the ADAMTS7 locus were observed to have similar gene-smoking interactions on CHD risk. Of the 5 smoking loci, variants at the CHRNA5 locus were found associated with CHD risk at GWAS levels of significance (P-value: 4x10-8). The reported lead variant for smoking behavior at CHRNA5 was associated with CHD only in “ever” or “current smokers” but not in “never-smokers” (P-value of interaction: 1x10-3).

Conclusions:
We report a novel association of the CHRNA5 locus with CHD and provide novel evidence for interaction effects of smoking behavior at the ADAMTS7 and CHRNA5 loci in relation to CHD. These findings are likely to provide novel biological and therapeutic insights into the etiology, risk and prevention of CHD.
Abstract 18170: The Impact of Systematic Implementation of SPECT Appropriateness Criteria on Procedures Utilization and Cost: A Prospective and Randomized Clinical Trial With One Year Follow-Up
Authors: Rodriguez Jaime , DeMuth Kaelin , Hernandez Marlow , Bush Howard , Fromkin Kenneth , Stubbe Hermann , Forzolli Nemer Dabage , Galindo Diana , Piloto Robert , Ciocon Jerry , Loquias Jesus , Russell Andrew , Gascon Jose A. , Aggarwal Alisha , Salguero Paola , Shen Michael
Published: April 2024

Background:
The SPECT Appropriateness Criteria (AC) has been used for the last 8 years to improve SPECT and subsequent procedure utilizations. However, there is no prospective trial data on the change of procedure volumes after systematic implementation of AC in the cardiology and primary care clinic settings on daily basis using Electronic Medical Records (EMR). MPI Optimization & Referrals (MORE) Trial is a single center, randomized and prospective study to investigate the long-term impacts of systematic implementation of AC on SPECT/subsequent invasive procedure volumes, clinical and financial outcomes.

Methods:
Consecutive 10,303 outpatients with 10 physicians were randomized into a control (CG) and interventional (IG) group. All patients were assessed using EMR and SPECT AC (2009). Recommendations to refer for SPECT in the IG were made only if patients were graded as Appropriate SPECT prior to their visits. No recommendations were made to CG. SPECT use through the 5-month study period was compared to the use 5 months prior to the trial as a baseline. All patients were followed for 1 year after initial AC assessment for subsequent catheterization, cardiac events (MI and death) and financial outcomes.

Results:
Compared to the baseline prior to the trial, SPECT volume had no change in CG, 64 to 68 (6%), but significantly increased in IG from 87 to 112 (29%, p < 0.01). Among patients in the IG group, there is a significant decrease in catheterization from 174 to 110 (37%) compared to 176 to 135 in CG (23%, p<0.002). No significant change in cardiac events (MI and death) between CG and IG in the 1-year follow-up. The cost is significantly decreased in the IG compared to the CG ($5,865±3,433 vs. $9,505±1,345) with the net average savings of $3,640 (38%, p< 0.001) per patient after 1 year.

Conclusion:
This is the first randomized clinical trial to demonstrate that systematic implementation of SPECT AC using EMR in cardiology and primary care setting on daily basis not only increased SPECT service volume appropriately but also lead to less subsequent invasive procedure utilization and lower the entire care cost without any significant changes of adverse cardiac outcomes. Further studies with long term clinical and financial outcomes are warranted.