bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18783: Contrasting Roles Of E2F2 And E2F3 in Endothelial Cell Growth and Ischemic Angiogenesis
Authors: Zhou Junlan , Qin Gangjian
Published: April 2024

Background:
Endothelial cell (EC) growth is essential for angiogenesis and ischemic tissue repair. The E2F family of transcription factors are master regulators of genes responsible for cell-cycle regulation; however, the specific roles of individual E2Fs in ECs are largely unknown. Here, we investigated the roles of E2F2 and E2F3 in EC growth, angiogenesis, and their functional impact on limb ischemia and myocardial infarction (MI).

Methods and Results:
We generated an endothelial-specific E2F3-deficient mouse strain, Tie2-Cre;E2F3
fl/fl
(EndoE2F3
Δ
/
Δ
). The animals were embryonic lethal with a penetrance equivalent to the global E2F3-knockout mice (live birth at ∼8% of the expected frequency). The survived EndoE2F3
Δ
/
Δ
mice grew to adulthood relatively normally, however, developed limb and toe necrosis (25% and 50%, respectively) after surgically-induced hindlimb ischemia and displayed a larger infarct size and worsened LV EF than Tie2-Cre;E2F3
+/+
littermates after surgical MI. Notably, in the ischemic tissues, the capillary density and rate of EC proliferation (BrdU staining) were significant lower in EndoE2F3
Δ
/
Δ
mice than in the controls. In contrast, E2F2
-/-
mice displayed better functional parameters after the surgical injuries and an increase in local vessel density and EC proliferation as compared to WT littermates.
Ex vivo
aortic ring assays confirmed that microvessel outgrowth was impaired in EndoE2F3
Δ
/
Δ
explants, however, enhanced in E2F2
-/-
explants. We then evaluated the roles of E2F2 and E2F3 on EC proliferation
in vitro
. ECs were isolated from lungs of the genetic mice, with E2F3
fl/fl
ECs being transduced with Adeno-Cre/GFP or Adeno-GFP. The E2F3
fl/fl
/AdenoCre-GFP ECs exhibited a dramatically lowered growth rate and reduced DNA synthesis than E2F3
fl/fl
/AdenoGFP ECs. Furthermore, the expression of E2F target genes, including CyclinA, Cdc2, Cyclin D, B-Myb, DHFR and Cdc6, was significantly downregulated in E2F3
fl/fl
/AdenoCre-GFP ECs. In contrast, E2F2
-/-
ECs displayed an increased rate of cell growth, DNA synthesis and the expression of E2F-regulated genes.

Conclusions:
E2F3 promotes while E2F2 suppresses ischemic tissue repair via reciprocal regulation of cell-cycle gene expression, EC proliferation and angiogenesis.
Abstract 18830: Increase in Platelet Reactivity After Red Blood Cell Transfusion in Coronary and Non-coronary Patients: Results from the Transfusion-2 Study
Authors: Silvain Johanne , Abtan Jeremie , Martin Rejane , Kerneis Mathieu , O'Connor Stephen A , Brugier Delphine , Barthelemy Olivier , Beygui Farzin , Collet Jean-Philippe , Montalescot Gilles
Published: April 2024

BACKGROUND: Red blood cell (RBC) transfusion increases platelet activation and aggregation in vitro in healthy volunteers. This provides a possible mechanism for the increase in recurrent ischemic events and mortality reported after RBC transfusion in acute coronary syndrome (ACS) patients. The aim of the study was to replicate these findings in coronary and non-coronary patients exposed to RBC transfusion.

METHODS: Platelet reactivity was measured before and 12 hours after RBC transfusion using light transmission aggregometry with four different agonists and Vasodilatator-Stimulated Phosphoprotein Platelet Reactivity Index (VASP-PRI) by flow cytometry. Consecutive and unselected patients were considered. Relative changes in maximum platelet aggregation (MPA) and in residual platelet aggregation assessed 6 minutes after initiation were considered as well as VASP-PRI.

RESULTS: Our study population consisted of 53 patients (45% of coronary patients) of whom 25 were on dual antiplatelet therapy (DAPT) (20 with clopidogrel and 5 with prasugrel) and 11 on aspirin alone. Transfusion led to a significant increase in MPA irrespective of the agonists used: 8.8% with ADP (52.1 ± 3.1 vs. 56.7 ± 2.8 p=0.03) and 12.5% with TRAP (46.8 ± 22 vs. 53.7 ± 24, p=0.02). A similar trend was observed with arachidonic acid and with the VASP PRI index (13.0 ± 23 vs. 16.5 ± 25, p = 0.2 and 46.3 ± 31 vs. 50.2 ± 27, p=0.3 respectively), although the difference was not significant. The impact of transfusion was more pronounced in patients exposed to DAPT (coronary patients) although P2Y12 Inhibitors provided lower levels of baseline platelet aggregation (Relative changes of +13.8%, p=0.02 with ADP, +24.5%, p=0.01 with TRAP, and +10%, p = 0.6 for the VASP-PRI).

CONCLUSION: Red blood cell transfusion increase platelet reactivity in patients. This effect is more pronounced among patients treated with P2Y12 inhibitors and may account for the detrimental effect of RBC in the context of ACS.
Abstract 18865: A Novel in vivo Model of Amyloidogenic Light Chain Induced Cardiac Toxicity in Zebrafish
Authors: Mishra Shikha , Guan Jian , Plovie Eva , Merlini Giampaolo , Connors Lawreen H , Seldin David C , MacRae Calum A , Liao Ronglih
Published: April 2024

Over 50% of amyloidogenic light chain (AL) amyloidosis patients present with cardiac involvement, characterized by fibril deposition in cardiac tissue, resulting in a rapidly progressing, fatal cardiomyopathy. Aside from cardiac transplantation, there are currently no targeted pharmacologic treatments available for cardiac amyloidosis. This is largely attributed to our limited understanding of the underlying molecular mechanisms of this disease, compounded by the lack of an
in vivo
model to study disease mechanisms. Previous work from our laboratory demonstrated that human AL- light chain (LC) proteins exhibit an inherent cardiac toxicity via a p38/MAPK dependent pathway, independent of fibril formation. Here we demonstrate a novel
in vivo
model of AL-LC cardiotoxicity in zebrafish. Zebrafish embryos were treated with AL-LC, Control-LC (Con-LC) or vehicle (Veh), injected directly into circulation via cardiac puncture. Consistent with our previous findings, AL-LC treatment elicited an increase in p38 activation. This was accompanied by increased cardiac cell death, as measured by Bax/Bcl2 ratio and TUNEL staining of isolated zebrafish hearts. Additionally, AL-LC treated embryos exhibited a decrease in cardiac output. Strikingly, AL-LC treatment resulted in a marked loss of survival (Figure 1), with 100% mortality at 13 days. Our lab recently identified a major role for stanniocalcin1 (STC1) in the pathogenesis of AL-LC-induced cardiotoxicity. STC1 expression was significantly increased by AL-LC treatment, but not by Con-LC. Morpholino-mediated silencing of STC1 expression protected against AL-LC induced cardiotoxicity, preventing cardiac cell death and mortality.Collectively, this work establishes a novel zebrafish model of cardiac amyloidosis, and identifies STC1 as a critical determinant of AL-LC mediated toxicity, demonstrating its requirement in downstream signaling pathways associated with AL-LC induced cardiac toxicity. .
Abstract 18879: Procedural Success in the CONFIRM Trial is Independent of Use of Irrigated or Non-irrigated Ablation Catheters
Authors: Krummen David E , Schricker Amir A , Lalani Gautam , Baykaner Tina , Narayan Sanjiv M
Published: April 2024

Introduction:
Irrigated ablation catheters have become the preferred radiofrequency (RF) catheter for atrial fibrillation (AF) ablation due to greater energy delivery, particularly in areas of low blood flow. We hypothesized, however, for AF ablation not routinely incorporating mitral isthmus ablation (and therefore minimizing ablation within the coronary sinus), that non-irrigated ablation catheters would be non-inferior to irrigated catheters.

Methods:
We analyzed the results of the CONFIRM (Conventional Ablation for Atrial Fibrillation With or Without Focal Impulse and Rotor Modulation, FIRM) trial with respect to type of ablation catheter used: irrigated (8.5 French, Thermocool, Biosense-Webster, Diamond Bar, CA) and non-irrigated (8 French, 8-mm tip, Blazer XP, Boston Scientific, Natick, MA). We analyzed the FIRM-guided and FIRM-blinded ablation limbs separately; analysis was performed on an intention-to-treat basis, and crossovers were not permitted. Statistics were calculated using SPSS Version 19 (IBM, Armonk, NY).

Results:
In 92 patients (age 62±9 y, EF 54±14%) undergoing 107 consecutive ablation procedures, overall freedom from AF and all atrial tachyarrhythmias (ATs) was 70.6% in the FIRM-guided and 39.1% in the FIRM-blinded limbs (p=0.003). Freedom from AF and ATs with the non-irrigated catheter was 87.5% in the FIRM-guided and 42.1% in the FIRM-blinded limbs, while with the irrigated catheter was 58.3% and 25.0% respectively, thus meeting the criteria for non-inferiority. The figure shows arrhythmia-free survival in the FIRM-guided limb of the CONFIRM trial for irrigated and non-irrigated catheters.

Conclusions:
The CONFIRM trial showed significantly improved ablation results with FIRM-guided ablation, independent of the use of irrigated or non-irrigated ablation catheters. Future studies should examine if similar outcomes are seen with other ablation energy sources such as cryoablation or high-frequency ultrasound.
Abstract 18894: Global Left Ventricular Remodeling Characteristics are More Important than Scar Extent and Location for Prediction of Severe Mitral Regurgitation in Advanced Ischemic Cardiomyopathy
Authors: Cavalcante Joao L , Saleh Qusai , Adeniyi Aderonke , Thavendiranathan Paaladinesh , Popovic Zoran B , Starling Randall C , Desai Milind Y , Flamm Scott D , Marwick Thomas H , Kwon Deborah H
Published: April 2024

BACKGROUND:
Mitral regurgitation (MR) is particularly common in patients with ischemic cardiomyopathy (ICM) following an acute myocardial infarction where its presence is independently associated with worse mortality. In patients with advanced ICM, unfavorable LV remodeling causes geometrical changes leading to MR development. The best management of these patients remains unclear. Whether magnetic resonance imaging (MRI) with its higher spatial resolution and scar information can add further insights remains unknown.

HYPOTHESIS:
We hypothesized that MRI assessment of LV remodeling as well as scar extent, location and papillary muscle involvement could aid in the prediction of severe MR in patients with advanced ICM.

METHODS:
A total of 452 patients with LVEF ≤ 40% and ≥ 70% stenosis in ≥ 1 coronary artery, history of CABG or PCI with transthoracic echocardiogram and MRI studies within 7 days were included (median=1 day). Quantitative MR assessment was performed as per ASE guidelines. LV volumes, sphericity and LVEF were calculated from cine MRI images. LV scar was measured ∼ 10-15 minutes after gadolinium injection, using phase-sensitive inversion recovery sequence.

RESULTS:
The mean age was 62 ± 10 years and males represented 75%. LVEF, LV end-systolic volume index were 23 ± 0.5% and 115 ± 2 ml/m
2
respectively. MR was classified as: trivial/mild (63%), moderate (22%) or severe (15%). Multinomial logistic regression analysis revealed that LV remodeling changes were independent predictors of severe MR but not scar extent, location and/or papillary muscle involvement (Table).

CONCLUSION:
In ICM patients with severely dilated LV, contrary to prior studies showing the importance of regional LV remodeling and scarring, global LV remodeling appears to be more important in predicting presence of severe MR. These findings further confirm the dynamic nature of the remodeling process and highlight its importance as future target for management of these patients.
Abstract 18962: MrpL48 is Associated with Impaired Mitochondrial Function and Blood Pressure Regulation in Genetic Hypertension
Authors: Maatz Henrike , Monti Jan , Goesele Claudia , Breiderhoff Tilmann , Pravenec Michal , Willnow Thomas , Sack Michael , Hubner Norbert
Published: April 2024

BACKGROUND:
Aerobic metabolism has been implicated in the pathogenesis of cardiovascular diseases but the underlying genes that contribute to this process are incompletely understood. Here, we identified a novel gene within a previously mapped blood pressure QTL on rat chromosome 1 and demonstrate that the nuclear encoded mitochondrial ribosomal protein 48 (MrpL48) contributes to impaired aerobic metabolism and elevated blood pressure phenotypes in rats and mice.

METHODES:
We measured telemetric blood pressure and generated genome wide expression signatures in kidneys of 30 rat recombinant inbred strains that were established from the spontaneously hypertensive rat (SHR) and the BN normotensive reference strain as well as from chromosome 1 congenic rats spanning the chromosome 1 blood pressure QTL. This led to a positional candidate gene which was subsequently analyzed at the molecular level. We investigated mitochondrial bioenergetic processes and translation in vitro and ex vivo and subsequently monitored blood pressure in MrpL48 knockout mice by telemetry.

RESULTS:
Expression analysis in the congenic line as well as the HXB/BXH recombinant inbred panel showed that variation at the MrpL48 locus resulted in altered gene expression and significantly correlated with blood pressure levels. We demonstrated that MrpL48 plays an important role in mitochondrial translation and subsequently mitochondrial function in vitro and in vivo. MrpL48 knockout mice showed significantly increased pulse pressure levels.

CONCLUSION:
Our findings suggest that MrpL48 plays an important role in mitochondrial dysfunction and blood pressure regulation and identifies a so far unappreciated mechanism of blood pressure regulation.
Abstract 18980: Cardioprotective Role of NO Derived from Sodium Nitrite in Attenuating Severity of Chronic Ischemia-Induced Heart Failure
Authors: Bhushan Shashi , Kondo Kazuhisa , Zlatopolsky Maxim A , Greer James J , Calvert John W , Lefer David J
Published: April 2024

Background:

Nitric oxide (NO) bioavailability is reduced in the setting of congestive heart failure. Nitrite (NO
2
) is a critically important NO intermediate that is readily metabolized to NO during ischemic conditions. We have previously demonstrated that NO
2
-
ameliorates acute myocardial ischemia/reperfusion (MI/R). However, no evidence exists as to whether increasing NO bioavailability through NO
2
-
therapy attenuates chronic heart failure following acute myocardial infarction.

Methods:

Male C57/BL6J Mice (n=13-15 per group) at 12-14 weeks of age underwent 60 min. of myocardial ischemia (MI) induced by transient LCA occlusion followed by 4 weeks of reperfusion. Sodium nitrite (NaNO
2
) or saline vehicle (VEH) was administered at a dose of 165 µg/kg (intracardiac injection) at reperfusion and then daily for 4 weeks in the drinking water (50 mg/L or 100 mg/L). Two-dimensional echocardiography was performed at baseline and 4 weeks post MI to assess left ventricular (LV) dimensions and ejection fraction (EF). Myocardial and blood NO metabolite levels were measured using HPLC and chemiluminescence methods.

Results:

Both circulating and cardiac NaNO
2
levels were increased in mice treated with oral NaNO
2
. Furthermore, NaNO
2
(100 mg/L) significantly preserved LVEF (47 ± 4% vs. 32 ± 4%, p < 0.01) and improved left ventricular LV dimensions (LVEDD/LVESD; 4.0/3.1 mm vs. 4.5/3.9 mm, p<0.05) at 4 weeks when compared to VEH.

Conclusions

: These data demonstrate that sodium nitrite therapy significantly improves LV function during heart failure following acute myocardial infarction. Studies are currently underway to define the cellular and molecular mechanisms by which NO derived from NaNO
2
protects the myocardium in the setting of heart failure.
Abstract 19004: Sr-bi Deficiency is Associated with Dendritic Cell Retention in Arterial Atherosclerotic Plagues and Impaired Atherosclerotic Regression in Apoe-r61 Hypomorphic Mice
Authors: Zhang Yi , Trigatti Bernardo L
Published: April 2024

A deficiency in SR-BI, a major HDL receptor, results in accelerated arterial plaque development in ApoE-R61 hypomorphic mice, however the effect of a lack of SR-BI on atherosclerotic plaque regression is unknown. In SR-BI-knockout/ApoE hypomorphic (KO-H ) mice fed a high fat diet, aortic atherosclerosis developed much faster than in the SR-BI+/+ ApoE hypomorphic (control) mice. When these mice were switched from the atherogenic diet back to a normal diet, atherosclerotic plaques regressed over the course of 11 weeks in the control mice, but not in KO-H mice, in which the plaques continued to develop. Dendritic cells (DC's) have been found to be involved in atherosclerosis development and regression. Immunohistofluorescence analysis revealed a large number of CD11c-positive DC’s which persisted within atherosclerotic lesions of KO-H mice, even 11 weeks after the diet switching. These CD11c-positive cells exhibited apparently attenuated expression of CCR7, a major chemoattractant receptor in DCs. To determine if SR-BI in macrophages or DC’s themselves might be required for plaque regression, bone marrow (BM) was transplanted from either KO-H or control donors into irradiated ApoE-hypomorphic recipients. Plaque regression was decreased in the mice transplanted with BM from KO-H donors, confirming a role for SR-BI in BM-derived cells in plaque regression. In cultured human DC's derived from THP-1 cells, HDL dose-dependently stimulated migration. HDL-stimulated migration of DC's was abolished by a SR-BI blocking antibody, PI 3-kinase inhibitors or using BM-derived DC's from SR-BI or PDZK1 KO mice, suggesting the involvement of an HDL-triggered PI3K signaling pathway emanating from SR-BI and its cytosolic adaptor protein PDZK1. Cholesterol loading of DCs impaired migration in response to HDL or CCL19, a ligand for CCR7; this was reversed by overnight incubation with HDL. Furthermore, incubation with HDL for 24 h induced a remarkable increase in expression of CCR7 and SR-BI in DC's. Taken together, the results suggest that SR-BI may mediate the migration of DC's facilitated by HDL, and is required for atherosclerotic plaque regression.
Abstract 19005: PGC1α Play a Critical Role in TWEAK Mediating Cardiac Dysfunction
Authors: Shi Jianru , Jiang Bingbing , Qiu Yiling , Guan Jian , Cao Xin , Su Lihe , Burkly Linda C , Kelly Daniel P , Liao Ronglih
Published: April 2024

Inflammatory cytokines contribute to the pathogenesis of cardiac dysfunction and symptomatic heart failure (HF). We recently identified that a novel TNF superfamily member, tumor necrosis factor-like weak inducer of apoptosis (TWEAK), was increased in patients with HF. Genetic overexpression of TWEAK in mice results in dilated cardiomyopathy and HF. This study was performed to investigate the molecular mechanisms underlying TWEAK-induced cardiomyocyte dysfunction.

Methods and Results.
Circulating levels of TWEAK were increased in mice through IV injection of recombinant TWEAK (r-TWEAK). r-TWEAK resulted in cardiac dysfunction and deleterious remodeling in a dose dependent manner. Histologic examination of r-TWEAK hearts revealed severe mitochondrial damage. In conjunction with mitochondrial pathology, genes required for mitochondrial oxidative phosphorylation were downregulated with r-TWEAK treatment. Importantly, PGC1α, a key regulator of mitochondrial gene transcription was downregulated in r-TWEAK hearts prior to the onset of cardiac dysfunction, suggesting a potential causal relationship. In isolated adult rat cardiomyocytes, r-TWEAK recapitulated contractile dysfunction, suggesting a cell autonomous mechanism. Adenoviral-mediated overexpression of PGC1α maintained mitochondrial levels in r-TWEAK-treated cardiomyocytes and protected against r-TWEAK induced contractile dysfunction, as revealed by percent cell fraction shortening experiments (control 4.23±0.22%; r-TWEAK 2.73±0.31%, p<0.05 vs. control; PGC1α+r-TWEAK 4.23±0.25%, p<0.05 vs. r-TWEAK). Using shRNA mediated genetic silencing and adenoviral-mediated overexpression, we further implicate the upstream signaling molecule TRAF2, and the downstream regulator NFκB in TWEAK regulation of PGC1α, mitochondrial levels, and cardiomyocyte dysfunction.

Conclusion.
Our data identify TRAF2-NFκB-PCG1 axis as a critical molecular mechanism to the development of TWEAK-induced cardiomyocyte dysfunction and the development of HF. Modulation of mitochondrial levels or antagonism of TRAF2-NFκB may serve as candidate therapeutic targets for the treatment of heart failure.
Abstract 19030: Apolipoprotein C-III is Significantly Reduced by Prescription Omega-3 Free Fatty Acids (Epanova) in Patients with Severe Hypertriglyceridemia and Changes Correlate with Increases in LDL-C: A Sub-analysis of the EVOLVE trial
Authors: Rader Daniel J , Dunbar Richard L , Maki Kevin C , Jacobson Terry A , Kling Douglas , Davidson Michael H
Published: April 2024

Background:
Apolipoprotein C-III (apoC-III) inhibits lipoprotein lipase activity and hepatic uptake of triglyceride-rich lipoproteins. Elevated levels of apoC-III have been found to be an independent predictor for CHD risk and genetically reduced apoC-III is associated with protection from CHD, making apoC-III a therapeutic target. Omega-3 fatty acid formulations containing docosahexaenoic acid (DHA) have been shown to increase LDL-C in patients with severe hypertriglyceridemia (HTG). Clinical data suggest that eicosapentaenoic acid (EPA) alone, which lowers triglycerides to a similar extent as EPA + DHA, does not raise LDL-C, but also fails to lower apoC-III. Materials: The EVOLVE trial evaluated 2, 3, and 4 g/d of a novel omega-3 free-fatty acid (FFA) formulation containing both EPA + DHA compared with 4 g/d of olive oil. In 399 patients with severe HTG we evaluated the effects on plasma apoC-III levels and the correlations between change in apoC-III and change in plasma lipids (TG, LDL-C) after 12-weeks of therapy.

Results:
Epanova 2, 3, and 4 g/d produced significant median reductions in apoC-III by 9 (p=0.02), 13 (p=0.006), and 15% (p<0.001), respectively, compared to olive oil (+5%). Epanova produced significant (p<0.001) median reductions in triglycerides (TG) of 26, 22, and 31%, respectively, compared to 10% for olive oil, and significant (p<0.001) median increases in LDL-C of 21, 16, 26%, respectively, compared to 10% for olive oil. There was a significant positive correlation between percent changes in apoC-III and triglycerides (r=0.603, p<0.001) and a significant negative correlation between percent changes in apoC-III and LDL-C concentrations (r=-0.28, p<0.001).

Conclusion:
A novel omega-3 FFA formulation containing both EPA and DHA significantly lowered apoC-III levels in addition to reducing TG levels. An increase in LDL-C correlated with the reduction in apoC-III. Since EPA alone does not appear to lower apoC-III, these results support the hypothesis that DHA has specific effects in lowering apoC-III and that the mechanism by which DHA increases LDL-C may be related to its effect to lower apo CIII.
Abstract 19060: An Anti-Viral Drug with Properties of Selective Inhibition of Adenylyl Cyclase Type 5 Reduces Infarct Size More when Delivered after than Before Reperfusion
Authors: Bravo Claudio , Yoon Seonghun , Kudej Raymond K , Tian Rong , Kolwicz Stephen , Buchholz Bruno , Gelpi Ricardo , Yoshiro Ishikawua , Iwatsubo Kosaku , Vatner Dorothy E , Yan Lin , Vatner Stephen F
Published: April 2024

There are at least two reasons why very few of the discoveries from genetically engineered mice have been translated to the clinics: 1.Most therapy requires delivery of a drug, since it is difficult to change a gene in patients; 2. Most cardioprotective agents require pretreatment before coronary artery (CA) reperfusion (R), but patients with myocardial infarction are rarely seen before CAR. We studied the drug 9-beta-D-arabinofuranosyladenine (Ara-Ade), previously used and FDA approved as an antiviral drug, because it has a structure resembling adenosine, but demonstrates selective adenylyl cyclase isoform type 5 (AC5) inhibition properties, i.e., it inhibits responses to beta-adrenergic receptor stimulation much greater in AC5 transgenic (Tg) mice than wild type, but not more in AC6 Tg and not at all in AC5 knockout, both in vitro and in vivo. We examined its ability to reduce infarct size (measured with TTC) after 30 min CA occlusion (CAO) and 24 hr CAR in mice. Surprisingly, infarct size, expressed as a fraction of the area at risk was lower, p<0.05, when the drug was delivered at CAR (16%), than when given before either CAO or CAR (21%) compared to vehicle (36%). p Ara-Ade also reduced infarct size in chronically instrumented conscious pigs, when delivered after CAR. In this model instantaneous measurements of coronary blood flow demonstrated that post reperfusion coronary hyperemia and reactive hyperemia, following a 15 sec CAO, were attenuated, consistent with isolated heart studies showing reduced coronary flow recovery after ischemia. Thus, a novel drug that inhibits AC5 induces even more cardioprotection when delivered after CAR than before, making it potentially more useful the clinical setting, where patients with myocardial infarction require CAR immediately after arriving at the hospital. It is conceivable that the mechanism, in part, involves protection of CAR damage, since the magnitude of coronary hyperemia after CAR has been related to CAR reperfusion damage.
Abstract 19062: Copeptin-to-BUN Ratio Predicts Outcome in Patients with Advanced Heart Failure: A key to the use of vasopressin antagonists?
Authors: Jarai Rudolf , Farhan Serdar , Schwarz Michael A , Huber Kurt
Published: April 2024

Background:
The arginine-vasopressin-aldosteron system is activated in patients with chronic heart failure and elevated serum concentrations of vasopressin as well as the c-terminal portion of its prohormone (copeptin) strongly predicts outcome of these patients. Re-absorption of urea by the kidneys is regulated by vasopressin and thereby it also influences blood urea nitrogen (BUN) concentrations. In the present study we investigated, whether the ratio of serum copeptin and BUN (copeptin-to-BUN) could be used to estimate long-term outcome of patients with chronic stable heart failure (CHF).

Methods:
We measured copeptin, BUN, high-sensitivity troponin T (hs-cTnT), plasma MR-proANP, MR-proADM and Nt-proBNP concentrations in 174 patients with CHF. Patients were followed for all-cause mortality and rehospitalization due to heart failure during a median time of 834days.

Results:
The ratio of copeptin-to-BUN was significantly higher among patients who died or were re-admitted to the hospital compared to those who remained event-free (0.86 vs. 0.45; p<0.001). In univariate Cox regression analysis, patients with copeptin-to-BUN ratio higher than the median had significantly higher risk of death or hospital re-admission than patients with lower copeptin-to-BUN ratio (HR 2.16 p<0.001; Figure). In multivariate analyses adjusted for several clinical variables and laboratory measures - including Nt-proBNP, MR-proADM, MR-proANP, hs-cTnT - the ratio of copeptin-to-BUN remained a highly significant determinant of long-term outcome (HR 1.645; p=0.023).

Conclusion:
In addition to well-established modern biomarkers, the copeptin-to-BUN ratio is a significant independent determinant of survival of patients with CHF. Future studies should evaluate whether copeptin-to-BUN ratio could be used to identify patients with advanced heart failure who might benefit from the use of vasopressin antagonists.
Abstract 19080: Association of Atrial Fibrillation Susceptibility Alleles and Intermediate Left Atrial and Pulmonary Vein Phenotypes and Their Impact on Catheter Ablation
Authors: Schönbauer Robert , Schmidl Josephin , Kosiuk Jedrzej , Fiedler Lukas , Ueberham Laura , Adams Volker , Dinov Borislav , Husser Daniela , Bollmann Andreas
Published: April 2024

BACKGROUND:
Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms (SNPs) on chromosomes 16q22 and 1q21 confer risk for atrial fibrillation (AF) but mechanisms and subsequent intermediate phenotypes remain elusive. Here, we analyzed the association between common AF susceptibility alleles and several left atrial and pulmonary vein phenotypes including left atrial and pulmonary vein dimensions and morphology and studied their impact on arrhythmia recurrence after AF ablation.

METHODS:
In 99 consecutive patients (mean age 61+/- 10 years, 68% male) undergoing catheter ablation for drug-refractory paroxysmal (48 %) or persistent (52 %) AF, left atrial and pulmonary vein dimensions were extracted from the preprocedural acquired multislice computed tomography (MSCT). Pulmonary vein anatomy was evaluated according to common trunk or additional veins. Left atrial voltage mapping was performed to identify scar and low voltage areas. Genotypes of rs7193343 (16q22) and rs13346333 (1q21) were determined. Serial 7-day Holter electrocardiographic recordings were acquired to detect AF recurrences.

RESULTS:
The presence of rs13346333 (1q21) was associated with a more spherical anatomy of the left atrium defined by the ratio of transversal to anterior-posterior diameter (OR: 0,138; 95% CI 0,022-0,856; p=0,033). In addition, rs7193343 (16q22) was associated with the presence of accessory veins (OR: 3,929; 95% CI 1,009-15,300; p=0,049). AF recurrence between 3 and 12 months occurred in 34,7 % of patients. Among the left atrial and pulmonary vein parameters, the presence of accessory pulmonary veins was associated with a significant lower risk of AF recurrence (OR: 0,587; 95% CI 0,461-0,748; p<0,001).

CONCLUSIONS:
This study suggests an association between AF susceptibility alleles and anatomic variations of the left atrium and pulmonary veins. Accessory pulmonary veins are dominant AF triggers and their ablation leads to AF elimination.
Abstract 19083: Predicting Aortic Valve Stenosis Progression: Discordance Between Anatomical and Hemodynamic Assessment of Aortic Valve Severity
Authors: Lee Glenn K , Soo Wern Miin , Ruan Wen , Chong Eric , Tay Edgar , Poh Kian Keong
Published: April 2024

Background:
The aortic valve area (AVA) is a marker of severity in aortic stenosis (AS) patients and has prognostic and treatment implications. However, there is limited data on predictors of severity progression.

Methods:
We analyzed 509 consecutive patients with AS who underwent paired echocardiographic studies >180 days apart. Anatomic and haemodynamic assessments of aortic valve stenosis severity were performed. Two hundred and sixty-seven patients (52%) had significant decrease (>20%) in AVA. We compare their baseline echocardiographic parameters to the group without progression.

Results:
The mean time interval between the paired studies (1252±910 days) and the mean LV ejection fraction (60±12%) were not significantly different between the two groups. One hundred and forty patients (28.8%) had mild AS (defined as AVA >1.5cm2), 217 (44.7%) had moderate AS (AVA 1 - 1.5 cm2) and 129 (26.5%) had severe AS (AVA <1.0 cm2); the decrease in AVA was greatest in those with mild AS (24.7% vs. 10.0% vs. 4.2%, p<0.001). Initial anatomic valve area but not pressure gradients predict progression (Table).

Conclusions:
The progression of AS appears fastest in those with mild AS. Determination of aortic valve area predicts progression. More frequent echocardiographic assessments may perhaps be performed in this group of patients for timely identification of patients who may benefit from subsequent intervention.
Abstract 19086: Pulmonary Hypertension Accompanied by Changes in Left Ventricular Structure and Function in End Stage Renal Disease Patients on Maintenance Hemodialysis
Authors: Blaschke Jon P , Skipper Betty , McClelland Sandra L , Fagan Kathleen , Begay Darlene , Harford Antonia A , Zager Philip G , Raizada Veena
Published: April 2024

Introduction:
Pulmonary hypertension (PH) is increasingly recognized in patients with end stage renal disease (ESRD) on hemodialysis (HD). The causes of PH include features characteristic of ESRD and HD including the hemodynamic effects of an AV fistula and left heart disease. Although LV abnormalities occur frequently in ESRD patients, the association of such abnormalities with PH has been rarely studied.
Hypothesis:
PH in patients on chronic HD is associated with LV structural and functional abnormalities, including LV diastolic dysfunction (LVDF).

Methods:
Ninety- four patients (age range, 23-77 years; females, 45) underwent Doppler echocardiography 10-12 hours after HD. PH was considered present when the pulmonary artery systolic pressure (PAP) was ≥ 40 mmHg. LV measurements included thickness of the interventricular septum (IVS) and posterior wall (PW); LV mass; LV size calculated from the LV internal dimensions at the end of diastole and systole (LVIDd and LVIDs); and LV systolic function from ejection fraction (EF). LVDF was assessed from mitral diastolic velocity waves: deceleration time (DT) of the early wave (E) and the ratio (E/A) of E and the late velocity (A).

Results:
Sixty- seven patients (71%) had PH whereas 27 patients (29%) had normal PAP (<40 mmHg). Systolic and diastolic blood pressures (155 ± 29 vs. 148 ± 25 mm Hg, p =0.3; and 82 ± 15 vs. 84 ± 13 mm Hg, p = 0.38) were similar in patients with PH and those with a normal PAP (NPAP). LVIDd (5.21 ± 0.88 vs. 4.87 ± 0.84 cm, p= 0.05); LVIDs (3.45 ± 0.96 vs. 3.07± 0.76 cm, p= 0.05); IVS and PW thicknesses (1.03 ± 0.15 vs. 1.09 ± 0.19 cm, p = 0.19; and 1.07 ± 0.16 vs. 1.12 ± 0.17 cm, p = 0.25); and LV mass,

(123 ± 38 vs. 113 ± 3 g/m
2
, p= 0.12) were all similar in PH vs. NPAP patients. The LVEF was lower in PH than in NPAP patients (46.4 ± 17.6 vs. 62.4 ± 14.4%, p < 0.001). Both groups exhibited DTs of > 200 ms (215 ± 47 vs. 257 ± 52 ms, p = 0.006), with no significant between-group difference in the E/A ratio (E/A 1.48 ±0.74 vs. 1.15 ±0.44, p=0.06).

Conclusions:
We observed a surprisingly high prevalence of PH among patients on HD. PH was associated with a moderate depression in LV systolic function in the absence of clear changes in LVDF. Further studies are warranted to clarify the role of LVDF in the pathogenesis of PH in HD patients.
Abstract 19116: Efficacy of a Small Molecule HDAC Inhibitor in a Model of Diastolic Dysfunction with Preserved Ejection Fraction
Authors: Cavasin Maria A , Demos-Davies Kim , Mascagni Paolo , Dinarello Charles A , McKinsey Timothy A
Published: April 2024

Heart failure (HF) is a major health problem and growing economic burden worldwide. Of the patients with HF, ∼50% suffer from heart failure with preserved ejection fraction (HFpEF), also known as diastolic HF. Current standards-of-care for systolic HF provide little to no benefit to patients with HFpEF. Histone deacetylase inhibitors (HDACi) have been shown to improve systolic function in a variety of rodent models of HF. However, the impact of HDACi on diastolic function remains poorly understood. This study assessed the efficacy of an HDACi in a rat model of HFpEF. Dahl salt-sensitive (DSS) rats were fed low salt (LS, 0.4% NaCl) or high salt (HS, 4.0% NaCl) diets for 10 weeks. Rats were treated either with vehicle (LS and HS groups) or the pan-HDAC inhibitor, ITF2357, at 3 and 30 mg/kg (HS groups). Serial echocardiography was performed to assess left ventricle (LV) dimensions and function. At study endpoint, pressure-volume analyses were performed to further quantify effects of HS and HDACi on hemodynamic properties. HS feeding caused hypertension, cardiac hypertrophy and diastolic dysfunction, as shown by a 30% reduction of E/A and E’/A’ from baseline (measured by flow and tissue Doppler), a 27% increase of isovolumic relaxation time (IVRT), and a significant increase in LV end-diastolic pressure (LVEDP). EF was preserved in HS fed animals. ITF2357 was well tolerated and did not cause hematological side effects. ITF2357 dose-dependently prevented diastolic dysfunction of the heart; E/A and E’/A’ decreased 14% and 5% from baseline with low and high doses of ITF2357, respectively. Efficacy of ITF2357 was also observed at the level of IVRT and LVEDP. HDAC inhibition-mediated improvement in cardiac function and hemodynamics occurred independently of effects on cardiac hypertrophy and systemic hypertension. These data suggest that HDACs play a critical role in the pathogenesis of diastolic HF and that small molecule HDAC inhibitor have potential as novel therapeutics for HFpEF
Abstract 19118: Motor and Cognitive Impairment Following Pediatric Heart Transplantation in the US
Analysis of Organ Procurement and Transplant Network Data
Authors: Smoot Leslie B , VanderPluym Christina , Gauvreau Kimberlee , Oliva Melisa , Singh TP , Almond Christopher
Published: April 2024

BACKGROUND:
Studies suggest the cognitive and motor performance of pediatric heart transplant (HT) recipients falls below population norms; though the incidence and risk factors for these observations are not well characterized. We sought to identify independent predictors of cognitive and motor impairment after HT based on predictors recorded at the time of HT.

METHODS:
OPTN data were used to identify all children <18 years of age with a post-HT neurodevelopmental screen available between 2007 and 2010, when the screen was mandatory for all children. Logistic regression was used to identify independent risk factors for definite or probable cognitive and motor impairment, respectively, as reported by transplant centers using a standardized screen.

RESULTS:
Of 1999 children with a cognitive screen available and 2048 children with a motor screen available, the median age at HT was 6 years, the median weight was 19.1 kg, 57% were white, 37% had congenital heart disease (CHD), 59% were listed UNOS status 1A at HT, 12% were ventilated, 11% were on VAD support, 43% had renal dysfunction, and 44% had Medicaid Insurance. Patients without screening data available were more likely to be younger at transplant but were otherwise similar. Overall, 15% of HT recipients were categorized as having definite (10%) or probable (5%)
cognitive
impairment; 7% had questionable impairment and 79% had no impairment. By contrast 10% were categorized as having definite (8%) or probable (2%)
motor
impairment; 5% had questionable impairment and 85% had no impairment. Multivariable risk factors for cognitive and motor impairment are summarized below.

CONCLUSION:
An important fraction of children demonstrate cognitive or motor impairment after HT. Younger age at HT, congenital diagnosis and invasive hemodynamic support were associated with impairments in both cognitive and motor performance. Hispanic race, renal dysfunction and Medicaid insurance were associated with cognitive impairment.
Abstract 19123: Brag2, An Arf6 Gef, Regulates Integrin-dependent Adhesion in Endothelial Cells and is Involved in Angiogenesis
Authors: Manavski Yosif , Carmona Guillaume , Bennewitz Katrin , Tang Zhongshu , Zhang Fan , Sakurai Atsuko , Gutkind Silvio J , Li Xuri , Kroll Jens , Dimmeler Stefanie , Chavakis Emmanouil
Published: April 2024

β1-integrins are essential for angiogenesis. However, the mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis are unclear. Brag2 is a guanine nucleotide exchange factor for the small GTPase ARF6, which is involved in the traffic of receptors and in the regulation of actin cytoskeleton. Here, we demonstrate that siRNA-mediated silencing of Brag2 reduced basal and VEGF-induced activation of Arf6 and significantly blocked basal and VEGF-induced angiogenic sprouting (by 40 ± 7 %), tube formation and 3-dimensional migration of EC. Transfection with Brag2 siRNA increased focal adhesions and enhanced adhesion of EC on β1-integrin ligands, such as fibronectin and collagen. In line with these results, silencing of Brag2 significantly increased the surface expression of the α5β1-integrin. Moreover, silencing of Brag2 significantly reduced the endocytosis of β1-integrins and specifically of the active (matrix bound) α5β1-integrin present in focal adhesions, suggesting that Brag2 may contribute to the disassembly of focal adhesions during migration via β1-integrin-endocytosis. Strikingly, in vivo silencing of the Brag2 orthologues in zebrafish embryos with morpholinos perturbed vascular development by leading to defects of the parachordal vessels, the dorsal longitudinal anastomotic vessel and the intersomitic vessels. Beyond developmental angiogenesis, in vivo silencing of Brag2 with intravitreal injection of shRNA significantly reduced pathological retinal neovascularization in the model of retinopathy of prematurity (32 % inhibition) and pathological choroidal neovascularization in a model of laser-induced choroidal neovascularization. These data reveal that the Arf6 GEF, Brag2 is essential for developmental and pathological angiogenesis probably by mediating EC migration and angiogenic sprouting through regulation of adhesion by promoting integrin internalization.
Abstract 19136: Incidence of Diabetes Mellitus in Patients with Congenital Heart Disease
Authors: Dellborg Mikael , Bjork Anna , Pirouzi Nabi , Ambring Anneli , Eriksson Peter , Svensson Ann-Marie , Gudbjornsdottir Soffia
Published: April 2024

Introduction:
Today 0.8-1 % of all children are born with congenital heart defects (CHD) and most live into adulthood, with estimations and registry data indicating that 90-95% of all CHD now reach adulthood. CHD may increase the risk of infections and subsequently higher risk of diabetes type 1. Diabetes type 2 (T2D) increases and CHD could lead to a more sedentary lifestyle with a higher risk of developing T2D. Rhe relation between CHD and diabetes has previously not been investigated.

Hypotheses:
We estimated the risk of developing diabetes in a large cohort of patients with CHD as found in the nationwide diabetes registry in Sweden, NDR

Methods:
the National Diabetes Registry, NDR has an estimated coverage above 70% for Sweden. We identified patients with CHD in the NDR and compared to two controls groups, control group 1 never hospitalized paired patients with T1D or T2D and a second control group randomly selected paired patients with diabetes T1D or T2D and previous hospitalization for any reason. Both control groups were adjusted by age and gender. The analyzed characteristics were age, gender, type of diabetes, diabetes duration, systolic blood pressure, BMI, waist measurement, HbA1c, smoking, microalbuminuria, antihypertensive, lipid lowering drug use and type of hypoglycaemic treatment.

Results:
We found 1860 patients in the NDR with CHD as additional diagnosis. With a presumed prevalence of between 0.3 and 0.4% of the adult population, diabetes was found in 6.2 to 8.2% of all adults with CHD, for an odds-ratio of 1.35 (1.3-1.4, p<0.001) for diabetes of any kind to occur in patients with CHD as compared to adults without CHD. CHD and diabetes with the Swedish population at age 18-100 years CHD Total pop OR P Total no 25.000 (est) 7.562.648 With diabetes 1860 425.375 with diabetes 7.4% 5.6% 1.35 (1.3-1.4) <0.0001 Conclusion. Based on estimated prevalence of adults with congenital heart disease in Sweden, the prevalence of diabetes seems to be higher in the CHD population than in the population without CHD, given an OR of 1.35.
Abstract 19178: Cardiac Rehabilitation in the Elderly: An Under Referred Population That Does Not Attend
Authors: Martin Billie-Jean , Haykowsky Mark , Hauer Trina , Southern Danielle A , Knudtson Merill L , Arena Ross , Stone James A , Aggarwal Sandeep
Published: April 2024

Introduction:
Elderly subjects have been shown in recent years to derive benefit from attending cardiac rehabilitation (CR). However, they are less likely to attend. Further, the dependency of CR referral on patient age has not been explored.

Methods:
The Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) database was used to obtain information on all patients. Subjects with at least one vessel CAD were considered as the pool of subjects to be referred. Patients were categorized according to age, <50 years, 50-60 years, 60-70 years, 70-80 years, and over 80 years of age. Rates of referral to and subsequent attendance at CR were compared across age categories. Logistic regression models were constructed to assess whether age predicted referral or attendance.

Results:
A total of 25,958 (24.6% female) subjects were included; of those, 3,266 (12.6%) were under 50 years of age, 6,330 (24.4%) were 50-60, 7,618 (29.4%) were 60-70, 6,798 (26.2%) were 70-80, and 1946 (7.5%) were over 80 years of age. Subjects in the higher age ranges had a greater prevalence of congestive heart failure and chronic obstructive pulmonary disease but lower prevalence of diabetes than their younger counterparts (all p<0.0001). Advanced age was associated with both decreased attendance and referral, though the association was stronger with referral (both p<0.0001, Figure 1). Relative to the youngest group, each age category had reduced referral in unadjusted and adjusted models (adjusted OR (95%CI): age 50-60: 0.86 (0.79, 0.95); age 60-70: 0.57 (0.52, 0.63); age 70-80: 0.34 (0.31, 0.38); age>80: 0.15 (0.13, 0.17)). Only the two oldest groups were less likely to attend.

Conclusions:
Advanced age represents a barrier to CR in two ways: one, elderly subjects are less likely to be referred, and subsequently less likely to attend. As elderly subjects have been shown to derive similar benefits from CR as their younger counterparts, age as a barrier to CR needs to be addressed.
Abstract 19206: Pressure Overload Induced Heart Failure Reduces Endogenous Hydrogen Sulfide (H2S) and Mitochondrial Respiratory Function but is Rescued by a Novel H2S Sulfide Donor
Authors: Kondo Kazuhisa , Bhushan Shashi , King Adrienne L , Gorjon Gabriel , Gorjon Gabriel , Lefer David J
Published: April 2024

Introduction:
Sustained hypertension induces cardiac hypertrophy and dysfunction with increased generation of reactive oxygen species (ROS) by the mitochondria and other cellular sources. Hydrogen sulfide (H2S) is a potent signaling molecule that has been shown to attenuate oxidant-mediated cardiac injury. We investigated the effects of hypertension-induced heart failure on endogenous H2S production, mitochondrial function, and left ventricular performance.

Methods:
Transverse aortic constriction (TAC) was performed in male, C57BL/6J mice (n=15-20 per group). Mice received a novel, orally active H2S donor (SG-1002 at 20 mg/kg/day) delivered in the diet at 1 week prior to TAC. Follow-up echocardiography was performed up to 6 weeks. H2S and the stable metabolite - sulfane sulfur - were measured. Additionally, 8-isoprostane levels in the heart and myocardial mitochondrial respiratory function were also assessed following TAC.

Results:
Control and SG-1002 treated mice exhibited equivalent hypertrophy (VEH; 1.35 mm vs. SG-1002; 1.34 mm) at 6 weeks following TAC, but SG-1002 mice exhibited significantly improved cardiac function (EF; 69% vs. 47%, p < 0.001). Interestingly, control mice exhibited significantly lower H2S and sulfane sulfur levels in the blood and heart compared to sham mice at 6 weeks following TAC. Treatment with SG-1002 partially rescued H2S and sulfane sulfur levels in the blood and heart. Control mice exhibited higher 8-isoprostane levels in the heart compared to sham or SG-1002 treated mice at 6 weeks following TAC. At 6 weeks following TAC, myocardial mitochondrial respiratory function was also reduced, but rescued by SG-1002 diet.

Conclusion:
Our results indicate that pressure overload induced hypertrophy attenuates endogenous H2S bioavailability as a result of increased oxidative stress and mitochondrial dysfunction. Restoring endogenous H2S with an oral H2S donor may be a potential treatment in the setting of hypertensive heart failure.