bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19114: Ultrasound-Targeted Delivery of microRNA-126 for Therapeutic Angiogenesis
Authors: Kuliszewski Michael A , Liao Christine , Rudenko Dmitriy , Lee Paul J , Shen Vanessa , Leong-Poi Howard
Published: April 2024

Introduction:
MicroRNA-126 (miR-126) is an endothelial-specific microRNA that regulates angiogenesis by blocking endogenous inhibitors of vascular endothelial growth factor (VEGF), Sprouty-related protein (SPRED1) and phosphoinositol-3 kinase (PI3K). We hypothesized that ultrasound-mediated delivery of miR-126 would result in improved angiogenesis in the setting of chronic ischemia.

Methods:
Naked mature miR-126 was synthesized for transfection of rat specific miR-126 (22bp). Unilateral hindlimb ischemia was created by left femoral artery ligation in F-344 rats (n=45). At day 14 post-ligation, microvascular blood flow (MBF) in the distal hindlimb muscles were assessed by contrast-enhanced ultrasound (CEU). Ultrasound-mediated gene delivery (UMGD) of miR-126 (1x109 cationic microbubbles + 2 μ g of miR-126) (n=12) or scrambled miR (miR-SCR) (n=12) was performed, with control animals (n=11) receiving no treatment. An additional group (n=10) received UMGD of miR-126 (2 ug) three times every 48hours (day14, day 16 and day18). CEU perfusion was re-assessed at day 28, and transfection was assessed by real time PCR.

Results:
At day 14, prior to miR-126 delivery, normalized MBF for the ischemic muscle was similarly reduced in all treatment groups (55-60% of normal). At day 28, MBF remained unchanged in control and miR-SCR treated groups (0.61±0.08 vs 0.62±0.09, and 0.59±0.06 vs 0.63±0.07, respectively. In miR-126 treated animals, MBF improved (0.59±0.07 vs 0.78±0.06, p < 0.001 versus control and miR-SCM). After triple delivery of miR-126, further improvement in perfusion was noted (0.58±0.04 vs 0.88±0.03, p < 0.001 versus control and miR-SCM, and p <0.01 versus single miR-126). Real time PCR showed a 14.3±3.4 fold increase over control at 3h post transfection of miR-126 that persisted to day 3 post-UMGD, and normalized by day7 (n=3 per time point).

Conclusions:
UMGD of miR-126 results in improved perfusion in the setting of chronic hindlimb ischemia. Multi-gene delivery of miR-126 showed an incremental angiogenic response as compared to single gene delivery.
Abstract 19125: Mortality and Risk Factors for Malignant Ventricular Arrhythmias in Carriers of the Phospholamban R14del Mutation
Authors: van der Zwaag Paul A , van Rijsingen Ingrid A , Nannenberg Eline A , Groeneweg Judith A , Christiaans Imke , van Gelder Isabelle C , Hauer Richard N , van den Berg Maarten P , Wilde Arthur A , van Tintelen J. Peter
Published: April 2024

Introduction:
The phospholamban (
PLN
) R14del mutation causes dilated and/or arrhythmogenic cardiomyopathy and is associated with an increased risk of malignant ventricular arrhythmias (MVA) and end-stage heart failure.

Objectives:
To determine risk factors that predict MVA in carriers of
PLN
R14del and to assess their mortality risk.

Methods and results:
With non-invasive tools (ECG, echocardiography, Holter, exercise testing, and magnetic resonance imaging), we retrospectively evaluated clinical risk factors for MVA, defined as cardiopulmonary resuscitation (CPR), appropriate ICD treatment, and sudden cardiac death, in a multicenter cohort of 295
PLN
R14del carriers. In a median follow-up period of 42 months (interquartile range: 6 to 111 months), 55 (19%) persons experienced a first episode of MVA: 8 persons received successful CPR, 38 received appropriate ICD treatment, and 9 persons died suddenly in the absence of heart failure. The youngest age at which an MVA was observed was 20 years (CPR). Independent risk factors for MVA were non-sustained or sustained ventricular tachycardia and left ventricular ejection fraction <45%, with hazard ratios of 2.4 (95% CI: 1.5-4.5) and 4.0 (95% CI: 1.8-9.1), respectively. In addition, we analyzed all-cause mortality (main outcome measure: standardized mortality ratio [SMR]). All-cause mortality of
PLN
R14del carriers was increased (SMR 1.7; 95% CI: 1.4-2.0) with significant excess mortality starting from the age of 25 years.

Conclusions:
Carriers of the
PLN
R14del mutation are at high risk for MVA and all-cause mortality. Implantation of an ICD could therefore be justified in
PLN
R14del carriers with a left ventricular ejection fraction <45%, even in the absence of ventricular arrhythmias. Excess mortality is observed starting from the age of 25 years. Cardiological screening of
PLN
R14del carriers is thus recommended to be initiated at the beginning of adulthood to prevent malignant outcomes.
Abstract 19140: Targeted Disruption of Endothelial Specific Molecule (ESM)-1 Results in Atrioventricular Valve Malformations Leading to Cardiac Dysfunction
Authors: Menon Prashanthi , Spokes Katherine , Beeler David , Janes Lauren , Aird William
Published: April 2024

Background:
Endothelial cell specific molecule-1 (ESM-1) or Endocan is a circulating dermatan sulphate proteoglycan secreted primarily by the vascular endothelium. Elevated levels of ESM-1 are observed in the plasma of patients during tumor progression and in inflammatory disorders like sepsis suggesting that it could be potential biomarker for endothelial activation or dysfunction. To date there have been no in vivo studies of ESM-1. In this study we investigated the in vivo functional role of ESM-1 by the targeted deletion of the gene in mice.

Methods and Results:
To determine the critical functions of ESM-1 in vivo, we generated a global ESM-1 knockout mouse by deletion of exon1 of the ESM-1 mouse gene. ESM-1 knockout mice were born at the normal Mendelian ratio but showed 50% perinatal mortality by postnatal day 3 (P3). Pathological analysis of mice that died at P2 revealed dilated atria engorged with blood and thrombi indicative of possible defect in cardiac contractility. Pulmonary and liver congestion were also observed in ESM-1 knockout mice. Furthermore, histopathological studies revealed structural abnormalities in atrioventricular valves (AV) with an ebstenoid tricuspid malformation and parachute mitral valve abnormality suggesting AV valve regurgitation in ESM-1 knockout mice. In contrast, the semilunar valves appeared normal. Fetal genes associated with cardiac stress response including atrial natriuretic peptide (Nppa), brain natriuretic pepetide (Nppb) and beta-myosin heavy chain (Myh7) were significantly up regulated in ESM1 knockout P2 hearts compared to controls.

Conclusion:
In conclusion, our findings demonstrate for the first time that targeted disruption of ESM-1 results in atrioventricular valve anomalies leading to cardiac dysfuction. Understanding the mechanisms and signaling networks through which ESM-1 regulates valve formation has implications in the field of congenital heart disease research
Abstract 19166: Major Gap Exists Between Races in Applying Published Guidelines for Primary Prevention of Sudden Cardiac Death; An ESCAPE Database Analysis
Authors: Aziz Emad F , Pamidimukala Chaithanya K , Bastawrose Joseph , Pratap Balaji , Pai Urvi , Kahn Jonathan , Muafa Haitem , Cho Eun Sik , Lizardo Ian , Jadeja Neville , Awad Anthony , Benjo Alexandre M , Javed Fahad , Herzog Eyal
Published: April 2024

Background:
We have developed a novel ESCAPE pathway and registry to monitor, evaluate and guide physician’s referral for patients who meet class I indication of ICD implantation.

Methods:
All heart failure (HF) patients admitted to an inner city hospital and presented to our imaging laboratories with LVEF ≤35% and met Class I criteria for an Implantable ICD were prospectively followed and included in this study. Number of implanted devices and patient outcome of death and HF readmissions were assessed at 24-month and compared between the races.

Results:
A total of 1087 enrolled in this registry including 472 (43%) African Americans (AA) and 205 (19%) Hispanics (H). AA patients had a mean age of 64 ± 15 years, 75% with hypertension, 33% diabetics, and 30% with coronary artery disease. At the end of the follow-up period, only 88 (22%) AA and 42 (25%) H patients underwent ICD implantation; yet 183 (38%) AA patients and 61 (29%) H Patients had adverse outcomes. These included 99 (20%) deaths and 109 (23%) HF readmissions for AA, patients and 31 (16%) deaths and 35 (17%) HF readmissions for H patients (Figure).

Conclusions:
This real world prospective study reveals the significant gap and underutilization of ICD among special race eligible patients who carry a worse outcome.
Abstract 19172: Nanoparticle Delivery of Rosiglitazone Confers Tissue-Selective PPARgamma Activation
Authors: Ramirez Maricela , Ananta narayanan Jeyarama S , Wang Jun , Di mascolo Daniele , Ren Yuelan , Collins Alan R , Lyon Christopher J , Decuzzi Paolo , Hsueh Willa A
Published: April 2024

Thiazolidinediones (TZDs) are potent, high-affinity PPARγ ligands widely used to promote insulin sensitivity that act, at least in part, by decreasing myeloid-mediated inflammatory processes. However, treatment with TZDs such as rosiglitazone (RSG) can promote edema, weight gain and cardiac failure, limiting their clinical utility. We hypothesized that RSG-loaded nanoparticles could reduce these side-effects by conferring tissue-selective drug delivery. To test this hypothesis we developed a methodology to engulf RSG in ~100nm polylactic-co-glycolic acid (PLGA) particles extensively used for nanoparticle based therapies. These particles are rapidly cleared from the circulation by phagocytic cells, and thus accumulate in tissues enriched in myeloid-lineage cells, such as liver, spleen and potentially atherosclerotic plaques and remodeling white adipose tissue (WAT) of obese subjects. To test the effects of RSG-loaded nanoparticles in vivo, male LDLR-/- mice (N=3-4/group) were randomly assigned to 1) high-fat diet (HFD) alone, 2) HFD supplemented with RSG (1.2g RSG/kg diet), or HFD and then retro-orbitally injected on days 1 and 2 with 100µg of nanoparticles containing 3) PLGA alone or 4) PLGA loaded with 50µg RSG (PLGA:RSG). Tissue samples were collected at day 3 post-treatment. RT-PCR analysis of PPARγ target genes found RSG, but not PLGA:RSG or PLGA, increased (P<0.05) WAT expression of ABCG1 and CD36 and kidney expression of SCNN1A, which may contribute to TZD-mediated edema. RSG and PLGA:RSG, but not PLGA, induced FABP4 in spleen and increased or trended to increase (P<0.01) ACO1, CD36 and FABP4 in liver. RT-PCR analysis of tissue samples obtained at day 6 post treatment also found increases or trends to increase in liver expression of CD36 and FABP4 in PLGA:RSG treated mice, indicating that RSG-inducible gene expression in whole-tissue persisted for at least 4 days post-treatment, and might persist longer in myeloid populations within this tissue. Taken together this data indicates that our PLGA nanoparticles can be used to selectively target RSG-mediated gene activation to specific tissues, and thus may represent a novel approach for targeting drug delivery to myeloid-rich tissues or sites, such as inflamed WAT or atherosclerotic plaque.
Abstract 19185: An Employer-Initiated Challenge to Improve Cardiovascular Health in the Workplace
Authors: Shay Christina M , Brown Diane , Lonewolf Hazel , Hite Debbie , Sunday-Allen Robyn
Published: April 2024

Introduction:
Concerted attention is focused on achievement of the AHA’s 2020 Strategic Impact Goal which is aimed at a 20% reduction in deaths due to heart disease and stroke. Innovative strategies for promoting awareness of cardiovascular (CV) risk and maintaining and improving CV health are needed for a variety of community-based settings. Objective: To describe an ongoing employer-initiated program aimed at evaluating the effectiveness and efficacy of a CV health intervention focused on maintaining and improving cardiovascular health in an occupational setting.

Methods:
Administrators from the Oklahoma City Indian Clinic (OKCIC) implemented a voluntary 9-month “Cardiovascular Health Challenge” based on Life’s Simple 7. The OKCIC is an urban healthcare facility for members enrolled in federally-recognized American Indian tribes. Participants were asked to complete My Life Check assessments of Life’s Simple 7 at the beginning, midpoint, and end of the challenge period and to donate a small financial contribution that will be pooled and awarded to the employee with the greatest changes in CV health at the completion of the program. Several program-based workplace resources have been provided to promote healthy behavior change, including an AHA-sponsored walking path at the clinic facility, encouraged daily walking breaks, Life’s Simple 7 materials posted throughout the workplace, pedometers, cooking classes and smoking cessation workshops. Participant feedback regarding program experiences will be solicited and adherence, efficacy and effectiveness will be evaluated.

Results:
Approximately one-third (n=44) of OKCIC clinic employees are currently enrolled in the CV health challenge. Initial assessments indicate that baseline My Life Check assessments prompted screening of CV health components for a large proportion of participants who were previously unaware of their CVD risk.

Conclusions:
Incentive-based workplace programs focused on improving CV health represent a unique opportunity to achieve progress towards achievement of the 2020 goals. Maximization of employer encouragement and co-worker camaraderie may be key factors for improved awareness of CVD risk and promotion of healthy behavior change in the workplace.
Abstract 19221: Rates of Arterial Revascularization in Patients Treated with Vorapaxar vs. Placebo in the TRA 2°P-TIMI 50 Trial
Authors: Bohula May Erin A , Bonaca Marc P , Scirica Benjamin M , Morais Joao , Nieminen Markku , Murphy Sabina A , Braunwald Eugene , Morrow David A
Published: April 2024

Vorapaxar is a selective antagonist of protease-activated receptor (PAR)-1 that potently blocks platelet activation by thrombin. Thrombin signaling also influences vascular endothelial and smooth muscle function via PAR-1. Antagonism of PAR-1 reduces restenosis in animal models, suggesting the potential for vorapaxar to influence atherosclerotic disease progression.

METHODS:
The TRA2°P-TIMI 50 trial was a randomized, double-blind, placebo controlled trial of vorapaxar 2.5mg daily in 26,449 patients with stable atherosclerotic vascular disease, including prior myocardial infarction, stroke or peripheral arterial disease. Eligible patients had either an MI or ischemic stroke within the prior 2 weeks to 12 months or claudication with an ABI less than 0.85 or prior limb revascularization. We evaluated the rates of arterial revascularization in all patients included in the trial.

RESULTS:
Patients treated with vorapaxar had significantly lower rates of any arterial revascularization over 3 years as compared to placebo (13.6% versus 15.5%, HR 0.89; 95% CI 0.83-0.95, p<0.001). Specifically, the rates of revascularization were significantly lower with vorapaxar for both peripheral (3.9% versus 5.2%, p<0.001) and coronary vascular beds (9.7% versus 10.4%, p = 0.044), including a reduced rate of coronary artery bypass grafting (CABG) (1.7% versus 2.0%, p = 0.038). Moreover, elective revascularizations were reduced with vorapaxar (8.4% vs. 9.4%, p = 0.041).

CONCLUSIONS:
In this secondary analysis from a large randomized placebo-controlled trial, vorapaxar significantly reduced all arterial revascularizations suggesting possible clinical relevance of antagonism of PAR-1 mediated effects on endothelial or smooth muscle cells, as well as platelets.
Abstract 19229: DICOM-Based Regional Strain Shows Greater Variability with Base-Apex Gradient than Global Strain in a Heterogenous Population
Authors: Anwar Shafkat , Negishi Kazuaki , Borowski Allen , Gladding Patrick , Popovic Zoran , Erenberg Francine , Thomas James D
Published: April 2024

Introduction:
Two-dimensional Strain (2D S) is a powerful technique to evaluate myocardial deformation. We compared S from images in raw Polar (P) format with the same images in DICOM (D) in adult & pediatric patients to test agreement.

Methods:
110 patients (55/110 pediatric, 80/110 normal LV function) had echocardiograms with a General Electric (GE) Vivid 7 or E9. 4,3 & 2-chamber LV apical views yielding 330 datasets were analyzed with EchoPAC (GE, v. 10.8.1) in P &Velocity Vector Imaging (VVI, Siemens, v. 3.5) in D by 3 blinded readers. Regional differences in longitudinal Strain (LS) were tested with Bland Altman analysis.

Results:
Mean Global Longitudinal S (GLS) by EchoPAC (P) was -18.1 +/- 4.4 & VVI (D) -15.3 +/- 4.1. D yielded lower absolute GS by mean of 2.8 (± SD 2.7, p < 0.0001). In regional analysis, P also consistently produced higher values than D for corresponding segments. There was greater variability in RS with a consistent base to apex gradient. RS differences between P & D data were lowest at the base (Difference 1, p <0.00001) and highest at the apex (Difference 5.5, p <0.00001), Fig. 1&2.

Conclusion:
In this large and heterogenous population, there is region-specific variability in RS from DICOM images compared to source Polar data. These differences average out in global S analysis. Further standardization among Strain platforms is necessary to minimize differences.
Abstract 19235: Infiltrating Macrophage-Derived Angiopoietin-Like Protein2 (Angptl2) Accelerates Abdominal Aortic Aneurysm by Inducing Chronic Inflammation and ECM Degradation
Authors: Tazume Hirokazu , Miyata Keishi , Horio Eiji , Sakaguchi Hisashi , Okamoto Ken , Kawasuji Michio , Oike Yuichi
Published: April 2024

Abdominal Aortic Aneurysm (AAA) is characterized by aneurysmal morphological changes with low-grade chronic inflammation of atherosclerotic aortic walls. However, molecular mechanism has not been elucidated well. We recently reported that Angptl2 mediates various chronic inflammatory conditions, such as rheumatoid arthritis, dermatomyositis, cancer, and obesity-related metabolic disorder. In this study, we examined whether Angptl2 contributes to the pathogenesis of AAA formation. Firstly, we found expression of Angptl2 and pro-inflammatory cytokines mRNA in aneurysmal lesion of AAA patients were significantly increased compared to the non-dilating lesion. Angptl2 protein was abundantly expressed in infiltrating macrophages but not expressed in other inflammatory cells. We next examined whether Angptl2 deficiency affects the AAA formation in Angptl2-knockout (KO) mice. Interestingly, on day 28 after surgery, the sizes of AAA in Angptl2 KO mice were significantly decreased compared to wild-type mice (p<0.01). And expression of TNF-α, IL-1β, IL-6 and MMP-9 mRNAs in tissues from the aortic wall of CaCl
2
-treated Angptl2 KO mice was markedly decreased compared with that seen in wild-type mice. To identify the culprit cells secreting Angptl2 in AAA lesion, we transplanted bone marrow (BM) cells from Angptl2 KO mice or littermate wild-type controls into lethally irradiated wild-type recipients. The sizes of AAA in the recipients of Angptl2-deficient BM cells were significantly attenuated compared to those in the recipients of wild-type control BM cells (p<0.01). Finally, to investigate whether macrophage-derived Angptl2 could alter expression levels of proinflammatory cytokines and MMP-9 in macrophages, we analyzed expression of pro-inflammatory cytokines in thioglycollate(TGC)-induced peritoneal inflammatory macrophages. Significant decreases in TNF-α, IL-1β, IL-6 and MMP-9 expression were observed in macrophages from Angptl2 KO mice compared with similarly treated wild-type mice. These results suggest that infiltrating macrophage-derived Angptl2 promotes expression of proinflammatory cytokines and MMP-9 in these cells, resulting in progression of AAA pathogenesis.
Abstract 19275: T-type Calcium Channel Overexpression in Mice Attenuates Recovery from Bupivacaine-Induced Cardiac Arrest
Authors: Khoche Swapnil , Barr Larry , Zhang Hongyu , Makarewich Catherine , Taghavi Sharven , Houser Steven
Published: April 2024

Background _
The cardiotoxicity from the local anesthetic bupivacaine is predominantly a result of sodium channel blockade, though calcium channel inhibition has been implicated as well. Mechanisms of reversal of this cardiotoxicity are unclear. We investigated the toxicity of bupivacaine on FVB isolated mouse hearts that were either wild type (WT) or overexpressors for T-type calcium channel (TTCC). We subsequently attempted reversal of cardiotoxicity with a combination of intralipid and epinephrine. We hypothesized that the increased calcium metabolism of the transgenic hearts would augment the adverse effects of bupivacaine.

Methods and Results _
Hearts from anesthetized WT and transgenic FVB mice aged 4 months were excised and placed on a Langendorff perfusion apparatus. The left atrial auricle was excised, the mitral valve was perforated, and a fluid-filled balloon was placed in the left ventricle to capture left ventricular pressure and heart rate data. After 10 min of baseline perfusion at an EDP of 10mmHg, bupivacaine was added at 100μM, causing arrest of cardiac activity for both mouse lines. After 3 min of cardiac arrest, the heart was perfused with a solution of bupivacaine (30μM), intralipid (0.2%) and epinephrine (0.15μg/ml) with cardiac recovery following. At baseline, there were no differences in left ventricle function between WT and transgenic mice. After recovery, the left ventricle end diastolic pressure in the transgenic mice was significantly higher (29.18 ± 4.05 mm Hg) than in the WT mice (17.15 ± 0.83 mmHg), P=0.02). Furthermore, the left ventricle developed pressure was significantly reduced (P=0.03) in the transgenic mice (28.61 ± 5.966 mmHg) when compared to WT (57.17 ± 8.052 mmHg). When incorporating heart rate, the Rate Pressure Product (HR x LVESP) was significantly decreased (P=0.03) in the transgenic mice (6455 ± 748.3) versus the WT (11396 ± 1646). Electrophysiological analysis revealed significantly increased suppression of calcium current in the L Type Calcium Channel (P=0.03)

Conclusions _
These data show that bupivacaine-induced cardiotoxicity is more difficult to reverse in hearts overexpressing TTCC, possibly reflecting a stronger inhibition of Calcium release from the Sarcoplasmic Reticulum in them.
Abstract 19282: NAT10 Mutaion Causes Ciliary Aplisia and Congenital Heart Disease Associated with Heterotaxy
Authors: Li You , Yagi Hisato , Onuoha Ezenwa O , Pazour Gregory , Leatherbury Linda , Tsang Michael , Lo Cecilia
Published: April 2024

Introduction:
We recently showed patients with CHD associated with heterotaxy can exhibit respiratory ciliary dysfunction (CD) similar to that of patients with primary ciliary dyskinesia (PCD) - a ciliopathy with airway mucociliary clearance defects. Exome sequencing analysis revealed known PCD causing mutation and rare coding variants in known PCD genes were enriched in heterotaxy patients with CD, suggesting a common etiology for heterotaxy and motile cilia dysfunction. Further interrogation for novel variants in non-PCD genes have uncovered one patient with a homozygous mutation in the acetyltransferase
NAT10
. In this study, we investigated the hypothesis that NAT10 may play an essential role in ciliogenesis and is required for left-right patterning.

Methods and Results:
Exome sequencing was carried out in heterotaxy patients with ciliary dysfunction. Coding variants were filtered against dbSNP and 1000 genome databases. Novel homozygous coding variant in
NAT10
(M638V) was identified in one heterotaxy patient with ciliary aplasia. This mutation is in a highly conserved residue of the HAT domain and is predicted to be deleterious. As
NAT10
is known to acetylate tubulin, a key structural component of cilia, this seems likely to be disease causing. Using human hertRPE cells, we showed shRNA knockdown of NAT10 resulted in the inhibition of primary cilia formation. We further did
NAT10
shRNA knockdown in ciliated human airway epithelial cells and showed complete repression of ciliogenesis. In contrast, reciliating airway epithelial cells treated with control shRNA formed normal motile cilia. Further analysis of zebrafish embryos after
Nat10
morpholino injections showed laterality defects consistent with heterotaxy, confirming a requirement for NAT10 in left-right patterning.

Conclusion:
We identified a novel homozygous
NAT10
mutation in heterotaxy patient with ciliary aplasia. We showed
NAT10
is required for both formation of nonmotile primary cilia and motile cilia in the airway. Studies in zebrafish embryos further suggest
NAT10
is required for motile cilia function regulating left-right patterning. Together these findings support the conclusion that
NAT10
mutation can cause heterotaxy and ciliary aplasia phenotypes.
Abstract 19323: Disruption of Adenylyl Cyclase Type 5, a Novel Target for Obesity, Diabetes and Diabetic Cardiomyopathy
Authors: Ho David , Yan Lin , Zhao Xin , Bravo Claudio , Stanley William , Vatner Dorothy E , Pessin Jeffrey , Vatner Stephen F
Published: April 2024

We have previously reported that an adenylyl cyclase type 5 (AC5) deficient mouse model (AC5 knock out, KO) lives one-third longer than wild type (WT) mice. Despite greater daily food intake the AC5KO mice weigh less than WT mice and are protected against cardiac stress. In addition, the AC5KO mice have the same molecular signature of caloric restriction, the most common effective intervention to increase healthy longevity.. Since caloric restriction improves metabolic profiles and protects against insulin resistance, obesity and diabetes, we placed 6-8 week old male AC5KO mice and their corresponding wild type littermates (WTL) controls on a 35.5% high fat diet (HFD) for 100 days. At sacrifice, fat deposits were reduced 36% in AC5KO and cholesterol levels were reduced from 131±9.9 mg/dl to 105±3.1 mg/dl, p<0.05. Indirect calorimetry demonstrated that the AC5KO mice had a 16.7% increase in oxygen consumption during the light cycle (p<0.01) and 29.2% increase during the dark cycle (p<0.01) compared to WTL on HFD, suggesting enhanced metabolic rate as the mechanism for decreased adiposity and body weight. AC5KO mice also displayed improved glucose tolerance with a 32% reduction in area under the curve concomitant with a 111% increase in whole body insulin sensitivity (insulin tolerance test). In parallel, conscious non-stressed euglycemic-hyperinsulinemic clamp studies confirmed the marked enhancement of glucose homeostasis and insulin sensitivity in the AC5KO mice. Moreover, WTL developed reduced cardiac function consistent with diabetic cardiomyopathy following high fat diet feeding (e.g., left ventricular (LV) ejection fraction fell from 71±2% to 53±2%) whereas AC5 KO mice had better preserved LV ejection fraction (61±3%). In addition, AC5 KO mice showed 33% decrease in cardiac fibrosis and 40% decrease in apoptosis compared to WTL on HFD. Thus, reduction of AC5 protects against obesity, diabetes and diabetic cardiomyopathy, suggesting that AC5 is a potential novel therapeutic target for the treatment of obesity, diabetes and associated cardiomyopathy.
Abstract 19332: Results of Transfemoral Transcatheter Aortic Valve Implantation in Partner-Like Patients - A Comparison with Real-World Patients - The Bonn-Essen Experience
Authors: Sedaghat Alexander , Al-Rashid Fadi , Sinning Jan-Malte , Konorza Thomas , Ghanem Alexander , Nickenig Georg , Wendt Daniel , Werner Nikos , Grube Eberhard , Thielmann Matthias , Jakob Heinz , Erbel Raimund , Kahlert Philipp
Published: April 2024

Background:
Transcatheter aortic valve implantation (TAVI) has rapidly evolved to the standard-of-care for inoperable patients with severe, symptomatic aortic valve stenosis and to an accepted treatment option for high-risk, but operable patients. However the randomized PARTNER trial excluded patients with conditions frequently encountered in our clinical practice (e.g. ejection fraction <20%, severe mitral regurgitation, recent coronary stenting, cerebrovascular accident within 6-months, bicuspid valve, severe aortic regurgitation, prior valve surgery, creatinine >3.0 mg/dl and/or hemodialysis).

Methods:
From 2006 to 2011, 485 high-risk patients (Age: 80 ± 7 years; AVA: 0.6 ± 0.2 cm²; log. EuroSCORE 22 ± 16%) underwent transfemoral TAVI (Edwards Sapien n=176, Medtronic CoreValve n=309). The patients were divided into a “PARTNER-like” group (n=272) and a “PARTNER-exclusion” group (n=213), on base of the published inclusion criteria of the PARTNER B cohort. Differences in perioperative, 30-day and 2-year survival were assessed by Kaplan-Meier survival analysis.

Results:
There was no statistical difference in patient-survival concerning site of treatment or the type of valve system. Patients in the “PARTNER-exclusion”- group had a worse two-year survival (Figure 1) than patients of the “PARTNER-like” group (83.8% vs. 77.5%, p=0.089). Also a non-significant trend towards a higher 30-day mortality (10.3% vs. 6.2%, p=0.102) was found in the exclusion group. The most frequent exclusion criteria were prior valve surgery (16%), followed by chronic renal failure (14%), severe mitral regurgitation (11%) and reduced ejection fraction (9%).

Conclusion:
In our two-center real world experience, TAVI patients who meet exclusion criteria for the PARTNER trial represent a cohort with higher long-term mortality. These findings emphasize the importance of optimal patient selection and might have implications on selection-strategies
Abstract 19356: Pulmonary Valve Replacement Can be Delayed in Repaired Tetralogy of Fallot Patients with Preserved RVEF
Authors: Ermis Peter , Franklin Wayne , Parekh Dhaval
Published: April 2024

BACKGROUND
Surgical pulmonary valve replacement (PVR) is common in repaired Tetrology of Fallot. PVR is indicated for right ventricle (RV) remodeling. Previous studies have found that RV size normalization is rare in larger RVs that exceed RV end-diastolic volume (RVEDV) 160 mL/m2.

METHODS
A retrospective chart review was conducted in patients > 18 years who had PVR at our institution from 2000-2011. Demographic and clinical data, pre and post-operative MRI, and ECG, were collected.

RESULTS
19 patients were included. Average age was 24.9 years (range 18-44y). Average age at PVR was 20.3 years (range 12-40y). Only 2 patients had a pre-operative RVEDV < 160 mL/m2, with one patient whose RVEDV normalized ( 160 mL/m2 normalized RVEDV following PVR. All 4 patients without significant post-operative pulmonary regurgitation and preserved RVEF normalized. All had pre-operative RVEDVs > 160 mL/m2, with three >190 mL/m2. Table 1 shows, overall RV volume and function improved significantly following PVR while QRS duration remained unchanged by paired t-test.

CONCLUSION
In contrast to prior studies, delaying PVR in patients with preserved RVEF may be a reasonable management strategy. Our findings suggest that in patients with preserved RVEF, PVR can be delayed until the RVEDV reaches 190mL/m2. In patients with preserved RVEF, PVR with RVEDV < 160 mL/m2 may not be warranted.
Abstract 19375: Does Pulmonary Vascular Remodeling Reverse after Restrictive Mitral Annuloplasty in Patients with End-Stage Heart Failure?
Authors: Kainuma Satoshi , Taniguchi Kazuhiro , Toda Koichi , Funatsu Toshihiro , Miyagawa Shigeru , Kondoh Haruhiko , Daimon Takashi , Masai Takafumi , Ueno Takayoshi , Kuratani Toru , Sawa Yoshiki
Published: April 2024

Background. Prognostic importance of pulmonary hypertension (PH) in patients with heart failure is well known, but its reversibility after restrictive mitral annuloplasty (RMA) is less well established. We assessed the potential reversibility of pulmonary vascular remodeling in relation to plasma B-type natriuretic peptide (BNP), a biomarker of left ventricular (LV) filling pressure and diastolic dysfunction, over time after RMA.

Methods. We studied 98 patients with moderate to severe PH [systolic pulmonary artery pressure (SPAP) >40 mmHg] who underwent RMA for ischemic cardiomyopathy (ejection fraction <40%) and functional mitral regurgitation, and were followed up at least 12 months (mean, 49±26 months). Cardiac catheterization (baseline, 1month) and serial assessments of Doppler-derived SPAP (d-SPAP) and LV end-systolic dimension (ESD), with blood samples for plasma BNP measurement were performed.

Results. At 1 month after RMA, pulmonary capillary wedge pressure (PCWP) and SPAP decreased from 22±7 to 16±6 mmHg and from 50±13 to 40±11 mmHg (p<0.0001 for both), respectively, while transpulmonary gradient (mean PAP minus PCWP) did not change (11±4 mmHg, p=0.56). Cardiac index increased from 2.5±0.6 to 2.7±0.6 l/min/m2 (p= 0.03), and pulmonary vascular resistance changed from 231±100 to 206±73 dynes sec cm-5 (p=0.03), suggesting partial reversibility of pulmonary vascular remodeling. Serial echocardiography showed that s d-SPAP changed from 55±14 at baseline to 37±11 at 1 month, to 40±14 at 1 year, and to 45±19 mmHg at 2 year (p<0.0001). LVESD decreased from 56±8 to 49±9, 48±10, and 48±10 mm, respectively (p<0.0001). Plasma BNP decreased from 741±372 to 283±234, 223±199, and 237±208 pg/ml, respectively (p<0.0001). The percent change from baseline to 1 month and 1 year in BNP were significantly associated with corresponding changes in the d-SPAP (r=0.314, p=0.009 and r=0.391, p=0.006, respectively).

Conclusion. Following RMA, PA pressures commonly and significantly decreased, with a modest reverse pulmonary vascular remodeling in most patients after 2 years follow-up. Progression of pulmonary vascular abnormality may be a potential therapeutic target to reduce the prevalence of subsequent right ventricular dysfunction after RMA.
Abstract 19423: Co-Transplantation of iPS Cell-Derived Cardiomyocytes and Mesenchymal Stem Cells for the Regeneration of Infarcted Myocardium
Authors: Neef Klaus , Drey Florian , Lenerz Vera , Fatima Azra , Stamm Christof , Liakopoulos Oliver J , Wahlers Thorsten , Saric Tomo , Choi Yeong-Hoon
Published: April 2024

Introduction:
In this study the regenerative potential of co-transplantation of cardiomyocytes derived from induced pluripotent stem cells (iPS-CM) and mesenchymal stem cells (MSC) was assessed in a mouse model of myocardial infarction.

Methods:
After induction of myocardial infarction in CL57BL/6 mice, either iPS-CM expressing EGFP and luciferase, or magnetically labeled MSC, or a combination of both or saline were transplanted intramyocardially. Cell retention of iPS-CM by in vivo bioluminscent imaging (BLI), and magnetically labeled MSC by MRI was performed sequentially over four weeks. MRI was also used for the assessment of left ventricular ejection fraction (LVEF) at weekly intervals. Hearts explanted 1, 2 and 4 weeks after transplantation were analyzed histologically to locate and quantify transplanted cells, evaluate infarction size and structural integration of iPS-CM.

Results:
Transplanted cells were tracked over the course of four weeks by BLI for iPS-CM showing a 80% decrease in luminiscence intensity and no loss of signal for MSC by MRI. LVEF increased significantly in the iPS-CM/MSC (55.7±2.3%) compared to MSC (47.6±1.9%; p<0.001) and sham (44.2±2.6%; p<0.001) groups at 4 weeks after transplantation. Infarct size was significantly decreased in iPS-CM/MSC (2.1±0.8 mm2) compared to MSC (5.0±1.9 mm2; p<0.02) and sham (8.4±3.4 mm2; p<0.01). Immunohistochemical analyses for α-actinin and connexin 43 revealed functional integration and structural maturation of iPS-CM.

Conclusion:
The synergistic effects of co- transplanted iPS cell-derived cardiomyocytes and MSC resulted in functional integration and structural maturation of iPS-CM and, in turn, improved recovery of heart function after myocardial infarction. This novel approach opens a new perspective for the regenerative therapy of the heart.
Abstract 19441: Novel Telecommunications Software for Two-Way Interaction during ST-Segment Elevation Myocardial Infarction Management Improves Door-to-Balloon Times
Authors: Sardi Gabriel , Satler Lowell , Loh Joshua , Torguson Rebecca , Kent Kenneth , Suddath William , Pichard Augusto , Waksman Ron
Published: April 2024

Background:
A pre-hospital electrocardiogram (ECG) improves the management of patients with ST-segment elevation myocardial infarction (STEMI). Current telecommunication systems do not permit real-time interaction with first responders in the field or with care providers at referring hospitals. Our institution has developed a novel telecommunications system based on a software application that is downloadable to multiple platforms to permit real-time, two-way video and voice interaction over a secured, Health Insurance Portability and Accountability Act (HIPPA) compliant network. Hypothesis: Use of the CodeHeart application (CHap) for patients with possible acute coronary syndrome (ACS) will reduce door-to-balloon (DTB) times of STEMI patients.

Methods:
All STEMI system activations after implementation of the CHap were prospectively entered into a database. Consecutive CHap activations were compared to routine activations as controls, during the same time period (03/14/2011 to 12/31/2011). System quality measures were calculated and compared using Student’s t test or the Mann-Whitney U test as appropriate.

Results:
A total of 360 STEMI system activations occurred. 62 (17%) employed CHap and 298 (83%) routine channels. DTB times were reduced by the use of CHap when compared to controls (95.3±35’ vs. 154.6±102.4’, p=0.0009) as were first call-to-balloon times (68.9±29.3’ vs. 91.7±40’, p=0.004), which highlights the efficiency of the system for transferred patients. The percentage of catheterization laboratory activations for a true STEMI was higher with the use of CHap, although this trend did not reach statistical significance. [CHap 38/62 (61.3%) vs. routine 148/298 (49.7%), p=0.12].

Conclusion:
The implementation of a two-way telecommunications system that allows for real-time interactions between interventional cardiologists and referring practitioners improves overall DTB time and transfer time. In addition, it has the potential to decrease the frequency of false activations, therefore improving cost-efficiency of a network’s STEMI system.
Abstract 19444: The Effect of Daily Feedback on Changes in Dietary Intake and Adherence to Fat and Energy Goals
Authors: Ambeba Erica J , Sereika Susan M , Styn Mindi A , Ye Lei , Zheng Yaguang , Beatrice Britney N , Maydak Laura K , Acharya Sushama D , Burke Lora E
Published: April 2024

Introduction:
Dietary self-monitoring is essential for successful weight management. Tailored feedback messages delivered in real-time can enhance motivation and improve dietary adherence. This study examined the effect of daily, tailored feedback messages on dietary intake and adherence to energy and fat goals in the SMART Trial, a 24-month behavioral weight loss study.

Methods:
Participants (N=210) were randomly assigned to self-monitor via a paper diary, personal digital assistant (PDA), or PDA that provided daily feedback messages based on self-monitoring entries. The message library was changed at 12 months to limit desensitization. To assess the effect of feedback, changes in dietary intake and adherence to energy and fat goals were compared between the groups that did (FB, n=70) or did not (NFB, n=140) receive feedback. Dietary intake was assessed every 6 months and modeled as percent change from baseline using linear mixed modeling. Marginal modeling with generalized estimating equations was applied to examine the probability of being adherent to energy and fat goals.

Results:
Participants (78% White, 84% female) had a mean age of 46.8 years and BMI of 34.0 kg/m
2
. At baseline, mean energy intake was 2090 kcal, and 33.7% of calories were from fat. At 24 months, FB group achieved significantly greater reductions in energy (-23.4% vs. -14.1%, p=.02) and saturated fat intake (-9.3% vs. 3.4%, p=.03) compared to the NFB group. Overall, a higher percent of the FB group was adherent; however, adherence declined at 12 months and then rebounded (see Figure).

Conclusions:
Receiving daily, tailored feedback messages appeared to enhance reductions in energy and saturated fat intake. The decline and later improvements in adherence in the FB group suggest that the message library may need to be changed more often. Findings suggest that daily feedback can improve dietary and self-monitoring adherence, important strategies in weight management and CVD prevention.
Abstract 19492: Adipose-Specific Gene Therapy Corrects Leptin Deficiency in vivo
Authors: O'Neill Sean M , Chen Shu-Jen , Sandhu Arbansjit , Hinkle Christine , Stephan Stephen , Johnston Julie , Reilly Muredach
Published: April 2024

Objective:
To develop an
in vivo
, systemic method of gene therapy specifically targeting adipose tissue. We assessed the hypothesis that adipose-specific gene therapy using adeno-associated viruses (AAV) can correct leptin deficiency
in vivo
.

Background:
Obesity is a major risk factor for developing coronary heart disease. Adipose is an endocrine organ critical for energy intake and expenditure. Available data on adipose is limited, in part, because of the difficulties in adapting experimental techniques to tissue with high lipid content. Few studies have investigated
in vivo
gene transfer in adipose tissue, and these studies used subcutaneous injections in obese mice.

Method and Results:
Tail vein iv delivery of genes to adipose tissue was assessed in healthy C57BL/6 mice injected with AAV serotype 8 (AAV8) containing the expression vector of interest. Mice were sacrificed 2-3 weeks after injection, and tissues were analyzed for transgene expression. Systemic delivery of a vector containing the GFP gene under control of a CMV promoter induced GFP transgene expression in most tissues, including all adipose depots tested. Replacing the CMV promoter with an adiponectin enhancer/promoter unit and incorporating liver specific micro-RNA-122 target sites into the vector restricted GFP expression to adipose tissue. The leptin gene was put into the adipose-targeted expression vector and delivered by AAV8 to 9-10 week old ob/ob mice. Phenotypic changes were then measured for 8 weeks. Expression of leptin gene was detectable in multiple adipose tissue beds at both RNA and protein levels in mice receiving AAV8 leptin vector, but absent in control mice. Mice receiving leptin gene ate less food and had lower insulin levels compared to control mice. At sacrifice, average weight of mice receiving leptin gene was 14 g less than control mice. Glucose tolerance tests demonstrated adipose-targeted leptin gene therapy increased insulin sensitivity in ob/ob mice.

Conclusion:
AAV8-mediated systemic delivery of an adipose-targeted expression vector can replace a gene lacking in adipose tissue and thus correct for leptin deficiency in ob/ob mice. This novel approach has therapeutic potential in obesity and downstream complications such as insulin resistance and diabetes.
Abstract 19495: Extraction of St. Jude Riata Leads: Clinical Experience and Outcomes at a High Volume Extraction Center
Authors: Sager Solomon J , Carrillo Roger G
Published: April 2024

Objectives:
St. Jude Riata leads were recalled December 2011. We sought to compare our procedural experience and outcomes extracting the Riata defibrillator lead with extraction of non-Riata leads.

Methods:
Data was obtained from 2008-2012 from a prospective lead extraction registry established at a single tertiary referral high volume extraction center. The experience with Riata extraction was analyzed and compared with extractions performed on non-Riata leads in a cohort of patients matched for comorbidities using the Charlson comorbidity index.

Results:
A total of seventy-two patients had Riata lead extractions, 35 for electrical malfunction and 37 for infections. There were 53 males (73.6%) and 19 females (26.4%). Flouroscopy before extraction revealed exteriorized cables on 15 patients (20.8%). Of patients with infections, 20 (54.1%) had vegetations ranging in size from 3-32 mm. Average age for Riata lead was 60 years old, and average ejection fraction (EF) was 42% +/- 8%. All leads were successfully extracted with no major complications. One patient developed a minor complication of arm swelling that resolved at two weeks. Rate of complications in the matched cohort of seventy two patients with extraction of non-Riata leads was .1%. There was no statistically significant difference in complication rates.

Conclusion:
Riata lead extraction is a safe procedure. Current techniques allow successful extraction in a majority of cases.
Abstract 19522: Trends and Outcomes in Mechanical Circulatory Support Among Medicare Beneficiaries
Authors: Khazanie Prateeti , Hammill Brad G , Eapen Zubin J , Curtis Lesley H , Hernandez Adrian F
Published: April 2024

Background:
Mechanical circulatory support (MCS) has emerged as a growing technology for patients with advanced heart failure, but diffusion and temporal trends of outcomes of this technology across centers is poorly understood.

Methods:
Using 2006-2010 Medicare inpatient claims, we identified all fee-for-service beneficiaries who received an implantable MCS device. Patients were excluded if they had major cardiac surgery or non-implantable MCS device within 30d prior to implant. Outcomes of interest were in-hospital mortality and, among those discharged alive, 30d and 1yr post-discharge mortality, transplant, and readmission. We also calculated the cumulative number of readmissions and inpatient days following discharge. Death and transplant were treated as competing risks for each other and for all other post-discharge outcomes.

Results:
We identified 1835 patients who received an MCS device. Annual implant volume increased from 176 in 2006 to 661 in 2010. Demographic characteristics of those receiving a device were consistent over time--mean age 59 years, 81% men, and 72% white. Elective admissions for an MCS increased over time (26% to 40%). Volume of cases per center varied but overall increased over time (Figure). In-hospital mortality decreased over time (30% to 12%, p<.001). There was a trend towards decreased 30-d readmissions with 32.5% in 2006 and 26.7% in 2010 (p=0.07). Among the 1549 patients discharged alive, observed post-discharge outcomes at 30d and 1yr were: post-discharge mortality 2.1%, 19.2%; heart transplant 2.3%, 29.5%; all-cause readmission 27.4%, 83.0%; cardiovascular readmission 11.4%, 48.8%; no. of all-cause readmissions 0.31, 1.98; and no. of inpatient days 3.2, 17.6, respectively.

Conclusions:
The volume overall of MCS and proportion of elective MCS implants has increased over time. Readmission and mortality outcomes have generally improved over time as implant volume has increased and the patient profiles have changed.