bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18515: Arterial Inflammation in HIV is Associated With Bone Marrow and Splenic Activation
Authors: MacNabb Megan H , Kaplan Rebecca S , Lavender Zachary R , Nitta Elaine , Deeks Steven , Martin Jeffrey , Hernandez Pampaloni Miguel , Ganz Peter , Hsue Priscilla , Tawakol Ahmed
Published: April 2024

Introduction:
HIV-infected individuals have increased arterial inflammation and higher risk of cardiovascular disease (CVD), likely related to chronic monocyte/macrophage (MΦ) activation. Arterial inflammation as assessed by
18
fluorodeoxyglucose (FDG) PET/CT correlates with MΦ activity and is predictive of CVD risk. Since MΦ that participate in atherosclerosis originate in the bone marrow and transiently reside in the spleen, we sought to evaluate the relationship between arterial inflammation and bone marrow and spleen activity in HIV using FDG-PET/CT.

Methods:
20 HIV-infected men and 20 non-infected controls (matched for age, gender and Framingham Risk Score) were studied. Individuals underwent PET-CT imaging and FDG uptake was quantified as standardized uptake values (SUV) in the bone marrow, spleen, wall of the ascending aorta, and control tissues (muscle and subcutaneous fat). For between-subject comparisons, SUV was corrected for blood background (SUVc).

Results:
The mean age (±SEM) of the participants was 54±2 years. Arterial inflammation was higher among HIV infected individuals vs. controls (SUVc:3.07±0.17 vs. 2.05±0.06,
p
<0.001, Figure 1a). Similarly, SUVc in both the bone marrow and spleen were higher among in HIV (2.87±0.28 vs 1.73±0.07 p=0.002 and 2.10±0.20 vs 1.56±0.05 p=0.006, respectively). Aortic SUV was strongly related to splenic SUV (r= 0.69,
p
<0.001, Figure1B) and bone marrow SUV (r=0.62, p<0.001) but was not associated with SUV of muscle (r=0.26, p=0.11) or fat (r=0.24, p=0.20).

Conclusions:
We demonstrate that arterial inflammation is increased in HIV-infected individuals and is positively associated with bone marrow and splenic activity. In contrast, FDG-uptake in control tissues does not correlate with arterial inflammation. Thus, up regulation of immune cell activity in the bone marrow and splenic reservoir may contribute to arterial inflammation in the setting of HIV infection.
Abstract 18516: Brag2, an Arf-GEF, Regulates Integrin-Dependent Endothelial Adhesion and is Involved in Developmental and Pathological 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. The mechanisms regulating integrin function in endothelial cells (EC) and their contribution to angiogenesis remain elusive. Brag2 is a guanine nucleotide exchange factor (GEF) for the small Arf-GTPases Arf5 and Arf6. The role of Brag2 in EC and angiogenesis and the underlying molecular mechanisms remain unclear. siRNA-mediated silencing of Brag2 significantly blocked basal and VEGF-induced angiogenic sprouting (by 40 ± 7 %), tube formation and migration of HUVEC (49 % inhibition). Transfection with Brag2-siRNA differentially affected α5β1- and αVβ3-integrin function: specifically, Brag2-silencing increased focal/fibrillar adhesions and EC adhesion on β1-integrin-ligands (fibronectin and collagen), while reducing the adhesion on the αVβ3-integrin-ligand, vitronectin. Consistent with these results, Brag2-silencing enhanced surface expression of α5β1-integrin, while reducing surface expression of αVβ3-integrin. Mechanistically, Brag2 mediated recycling of αVβ3-integrins and endocytosis of β1-integrins and specifically of the active/matrix bound α5β1-integrin present in fibrillar/focal adhesions (FA), suggesting that Brag2 contributes to the disassembly of FA via β1-integrin-endocytosis. Furthermore, we found that Arf5 and Arf6 are promoting downstream of Brag2 angiogenic sprouting, β1-integrin-endocytosis and the regulation of FA. In vivo silencing of the Brag2-orthologues in zebrafish embryos using morpholinos perturbed vascular development. Moreover, in vivo intravitreal injection of plasmids containing Brag2-shRNA reduced pathological ischemia-induced retinal and choroidal neovascularization. These data reveal that Brag2 is essential for developmental and pathological angiogenesis by promoting EC sprouting through regulation of adhesion by mediating β1-integrin internalization and link for the first time the process of β1-integrin endocytosis with angiogenesis.
Abstract 18519: Increased Mean Diffusivity (Brain Injury) Values in Insular, Hippocampal, Frontal, and Cerebellar Sites in Heart Failure
Authors: Woo Mary A , Kumar Rajesh , Fonarow Gregg C
Published: April 2024

While gray matter injury appears in heart failure (HF), the presence and extent of tissue injury impacting on autonomic, cognitive, emotional, and breathing regions is unclear.

Methods:
We performed diffusion tensor imaging in 16 HF (age, 55.1±7.8 years; LVEF, 27.7±6.7; 12 male) and 26 control subjects (49.7±10.8 years; 17 male), and assessed whole-brain mean diffusivity (MD) changes across the brain in HF compared to controls. Groups were compared between groups using ANCOVA, with age and gender as covariates.

Results:
Insular (HF vs controls; left insula, 1.08±0.09 vs 0.97±0.06x10-3 mm2/s, p<0.001; right insula, 1.06±0.11 vs 0.98±0.06x10-3 mm2/s, p=0.001), frontal cortices (left frontal, 0.96±0.05 vs 0.89±0.05x10-3 mm2/s, p<0.001; right frontal, 0.93±0.06 vs 0.87±0.05x10-3 mm2/s, p=0.001), hippocampal (left hippocampus, 1.18±0.26 vs 1.03±0.12 x10-3 mm2/s, p=0.04; right hippocampus, 1.33±0.40 vs 1.03±0.13x10-3 mm2/s, p=0.01), and cerebellar (left cerebellar, 0.90±0.09 vs 0.81±0.05x10-3 mm2/s, p<0.001; right cerebellar, 0.84±0.06 vs 0.78±0.03x10-3 mm2/s, p<0.001) MD values showed significant groups differences (increased MD values in HF, indicative of tissue injury) between HF and control subjects. Whole-brain voxel-based analyses showed multiple brain regions with tissue injury, including the left and right insular lobes, frontal cortices, hippocampal, and cerebellar sites (Figure; p = 0.005) that control autonomic, cognitive, emotional, and breathing processes.

CONCLUSIONS:
HF subjects show injury in the insular, hippocampal, frontal cortices, and cerebellar areas, sites which control autonomic, cognitive, emotional, and breathing functions. Injury in these areas may contribute to deficient functions found in the condition.
Abstract 18574: Examination of a Highly Penetrant Mouse Model of Bicuspid Aortic Valve Demonstrates that Endothelial Notch1 is Required for Proper Morphogenesis of the Aortic Valve
Authors: Bosse Kevin M , Koenig Sara N , Huang Hannah , Garg Vidu
Published: April 2024

Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1-2% in the population. BAV results in significant morbidity as it is one of the leading causes of valve stenosis and regurgitation in adults. We previously reported that mutations in the signaling and transcriptional regulator,
NOTCH1
, were a cause of BAV in non-syndromic autosomal-dominant human pedigrees. The Notch signaling pathway is critical for multiple cell differentiation processes, and Notch1 is expressed in the developing and adult aortic valve. Recently, we have generated a new highly penetrant mouse model of aortic valve malformations using
Notch1
haploinsufficient mice that are backcrossed in a
Nos3-null
background.
Notch1
and
Nos3
compound mutant adult mice (

Notch1
+/-
;Nos3
-/-

) display a nearly 100% incidence of BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. We have also found that by postnatal day 10, compound mutant mice suffer ~50% lethality compared to

NOS3
-/-

littermates. Here, we have examined

Notch1
+/-
;Nos3
-/-

embryos at serial timepoints to elucidate the mechanisms underlying BAV. Examination at embryonic day 18.5 (E18.5) demonstrated normal Mendelian ratios and histologic examination revealed thickened, malformed valve leaflets accompanied by other outflow tract abnormalities in

NOS3
-/-
;Notch1
-/+

mice, likely contributing to the neonatal lethality. Further investigation at E13.5 and E15.5 indicated that the

NOS3
-/-
;Notch1
-/+

aortic valve leaflets were significantly thicker than controls, suggesting that outflow tract cushion formation and early remodeling may be affected. In addition, we have generated mice are null for
Nos3
and haploinsufficient for
Notch1
in endothelial-derived cells using mice harboring a
Notch1
-floxed allele and Tie2-Cre mice. Our preliminary results indicate that

NOS3
-/-

;

Notch1
fl/+

;Tie2Cre
+
mice recapitulate the

NOS3
-/-
;Notch1
-/+

cardiac phenotype and suggest that endothelial
Notch1
is required for proper development of the aortic valve. Overall our data indicate that loss of endothelial Notch1 results in abnormal remodeling of the outflow tract cushions and contributes to BAV.
Abstract 18641: Relationship Between Effective Arterial Elastance and Specific Measures of Left Ventricular Afterload
Authors: Chirinos Julio , Shiva-Kumar Prithvi , Geraci Salvatore , Desai Sanjal , Chandrashekhar Rahul , Jain Snigdha , Saif Hassam , Haines Philip , Broderick Preston , Vakilipour Amin , Rawat Deepa , Witschey Walter , Ferrari Victor , Akers Scott
Published: April 2024

Background:
Effective arterial elastance (E
A
), the ratio of left ventricular (LV) end-systolic pressure and stroke volume, was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. In conjunction with LV end-systolic elastance, it is used to assess combined “ventricular-arterial stiffening”. However, theoretical modeling studies indicate that E
A
is not prominently affected by arterial stiffness or pulsatile load. However, empirical data assessing the relationship between E
A
and specific measures of arterial load are not available.

Methods:
We used multiple linear regression to assess the relationship between E
A
and arterial load determined non-invasively from time-resolved central pressure-flow analyses performed at rest in a diverse clinical population of adults (n=133). We also investigated the sensitivity of E
A
to detect changes in pulsatile load induced by isometric handgrip exercise (n=72) and by the administration of 0.4 mg of sublingual nitroglycerin (n=30).

Results:
Measurements at rest demonstrated that Ea was essentially a function of SVR (standardized β=0.99;
P
<0.0001), and heart rate (standardized β=0.18;
P
<0.0001), without significant contributions from aortic characteristic impedance (standardized β=0.0001;
P
=0.98), total arterial compliance (standardized β=0.007;
P
=0.63) or reflection magnitude (β=0.02;
P
=0.20). Despite pronounced changes in indices of pulsatile load induced by isometric exercise and sublingual nitroglycerin, changes in E
A
were unrelated to changes in indices of pulsatile load in response to either intervention (all R
2
<0.02). However, changes in Ea were essentially a linear function of the change in the SVR*heart rate product (isometric exercise R=0.98; nitroglycerin R=0.97; both
P
<0.0001).

Conclusions:
Our empirical findings demonstrate, in agreement with modeling studies, that E
A
is essentially a function of resistive afterload and heart rate and is negligibly influenced by (and insensitive to) variations in pulsatile afterload. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.
Abstract 18645: Rare SCN10A Variants Associated With Lone Atrial Fibrillation Modulate Peak and Late Sodium Currents
Authors: Savio Galimberti Eleonora , Weeke Peter , Vanoye Carlos G , Yang Tao , Kor Kaylen C , Atack Thomas , George Alfred L , Roden Dan M , Darbar Dawood
Published: April 2024

Introduction:
SCN10A
encodes the sodium channel isoform Nav1.8, which is variably expressed in atria and has been linked to altered cardiac conduction and atrial fibrillation (AF). We resequenced
SCN10A
in 274 lone AF probands and identified 18 heterozygous rare variants (6.6% prevalence). Based on evidence of AF co-segregation, initial assessment of functional importance, and presence in ≥1 lone AF proband, four single variants (Y158D, 417delK, R814H, A1886V) and a compound one (Y158D-R814H) were selected for functional studies. We tested the hypothesis that rare
SCN10A
variants modulate biophysical properties of Nav1.8 channel, providing a mechanism for enhanced AF susceptibility.

Methods:
SCN10A
variants generated by site-directed mutagenesis were transiently expressed in ND7/23 cells. Macroscopic currents obtained using voltage-clamp protocols were measured after 48 hr incubation at 37°C.

Results:
Variant 417delK showed near-total loss of current, and the remaining ones exhibited enhanced peak I
Na
and late sodium current (I
Na-L
) measured at 100 ms post-depolarization (gain-of-function). The magnitude of peak I
Na
density of variants A1886V (103.3±16.6 pA/pF, n=10) and Y158D (-81.9±7.2 pA/pF, n = 7) was ~2-fold larger than WT (-42.8±4.9 pA/pF, n=9, P<0.01), while R814H variant generated peak I
Na
density ~4 times larger than WT (-187±22.6 pA/pF, n=17, P<0.01). The effect of the compound variant was close to the average effect of both variants expressed independently (table).

Conclusion:
Rare
SCN10A
variants associated with lone AF displayed strikingly altered functional properties. There was both enhanced peak I
Na
and I
Na-L
(Y158D, R814H, and A1886V) as well as near-absent
SCN10A
-mediated Nav1.8 current (417delK). By demonstrating that rare
SCN10A
variants identified in subjects with lone AF markedly perturb Nav1.8 function
in vitro
, these studies provide further support for the hypothesis that these variants contribute to AF susceptibility.
Abstract 18652: Identification of Novel, Potentially Deleterious Variants in the ADAMTS7 Gene via Combined Exome and Sanger Sequence Analysis
Authors: Bauer Robert C , Xue Chenyi , Zhang Xuan , Do Ron , Kiss Daniel H , Kathiresan Sekar , Rader Daniel J , Reilly Muredach P
Published: April 2024

The ADAMTS7 locus has been identified in multiple recent genome-wide association studies as being associated with coronary artery disease (CAD) in humans. Based on these associations, we hypothesized that functional rare variants in the gene may be causal risk alleles for CAD in humans. In order to identify rare variants in the human ADAMTS7 gene, we used data from the NHLBI Exome Sequencing Project (ESP) of 6503 participants, which, as per Exome Variant Server (data release ESP6500SI-V2), identified 404 variants in the entire genic sequence of ADAMTS7, of which 169 were missense variants and 2 were nonsense variants. We acquired BAM files for the ADAMTS7 region in 5438 ESP samples and performed in-house realignment, filtering and variant calling for the ADAMTS7 gene using the following criteria; sequences needed ≥90% alignment to the reference sequence, as well as ≥2% better alignment to the actual ADAMTS7 gene vs. pseudogenes or else they were excluded from analysis. In these custom analyses we identified 103 missense and 2 nonsense variants. In addition, we performed Sanger sequencing of 200 PennCath patients (100 MI cases, 100 controls) using primer design that accounted for pseudogenes. For variant calling we only used data with 2X coverage in >50% of samples tested (19/28 amplicons). The Sanger sequence data revealed 27 missense and zero nonsense variants. Comparison of the custom analysis of ESP data and independent Sanger sequencing provided high-confidence calls for 12 coding variants (including the S214P variant, a lead SNP in the GWAS association) in the ADAMTS7 gene. In summary, several variants in the ADAMTS7 gene included in the Exome Variant Server appear to arise from pseudogenes, while a number of high-confidence ADAMTS7 variants are not included on the exome chip. By combining multiple sequencing technologies from multiple studies, we identified 12 variants located in the actual coding sequence of ADAMTS7 for future functional studies. In summary, pseuodogenes present a unique challenge to identifying coding variants in the age of exome and whole genome sequencing and require a customized strategy for sequence alignment and variant calling. ADAMTS7 provides a cautionary example and we present one approach to overcome these challenges.
Abstract 18654: Utility of Cardiac Stroke Score in a Prospective Study of Patients With Ischemic Stroke
Authors: Brown Rachel-Maria , Corado Carlos , Prabhakaran Shyam , Zhao Qiong , Maganti Kameswari
Published: April 2024

Background:
Ischemic stroke is a major cause of death and disability. Currently, the AHA/ASA guidelines recommend cardiovascular (CV) examination, cardiac enzyme tests, and a 12-lead ECG in all stroke patients. Combining the above parameters with echo, we developed a novel Cardiac Stroke Score (CSS). We investigated whether CSS can predict 1-month CV outcomes in a prospective cohort of ischemic stroke patients.

Methods:
We studied 333 patients (53.5% male; mean age 66.7 years) from an ongoing prospective stroke registry at Northwestern Memorial Hospital. The CSS was calculated based on serum troponin (<5, >5), ECG changes suggestive of ischemia (absent or present), wall motion abnormalities (absent or present) and ejection fraction (>50%, <50%), assigning a score of 0 or 1 for each of the parameters. Primary endpoints evaluated at 1 month were myocardial infarction (MI), recurrent stroke, readmission, other CV events, and cardiac death.

Results:
From the overall cohort, 9 patients (2.7%) had troponin >5, 115 patients (35%) had ischemic changes on ECG, 49 patients (15%) had wall motion abnormalities, and 43 patients (13%) had EF <50%. There appears to be a greater trend between the higher CSS and readmission, death and total CV events. Please see table 1.

Conclusions:
CSS appears to yield a predictive value in determining1 month CV events following an ischemic stroke. However, a larger cohort with more longitudinal follow-up is necessary to confirm our findings.

Table 1: One month CV outcomes for the cohort studied. (*= p<0.05)
Abstract 18676: Anti-miR33 Therapy Induces PGC1a Expression to Regulate Immunometabolic Pathways in Atherosclerosis and Obesity
Authors: Karunakaran Denuja , Thrush A. Brianne , Wu Zongbin , Geoffrion Michele , Ramphos Eleni , Moore Kathryn J , Harper Mary-Ellen , Rayner Katey J
Published: April 2024

Atherosclerosis and obesity are epidemic causes of morbidity and mortality, and immunometabolic mechanisms are at the intersection of both diseases. Recently, microRNA 33 (miR33) was identified as a novel and critical regulator of lipid metabolism and a therapeutic target for reducing atherosclerosis. However, the exact mechanism(s) by which anti-miR33 exerts these beneficial effects are unclear. Comprehensive microarray profiling of mRNA from atherosclerotic plaque macrophages of anti-miR33 treated mice identified PPARγ coactivator 1α (PGC1α) as a novel miR33 target gene that is markedly de-repressed. PGC1α is a key regulator of mitochondrial function and energy metabolism, and promoting its activity improves metabolic syndrome (e.g. insulin resistance, obesity, inflammation). Here, we determine if anti-miR33 therapy upregulates PGC1α and affects energy metabolism in atherosclerosis.

Results:
miR33 overexpression reduced the 3’UTR activity of PGC1α by 40% (p≤0.05), confirming it was a direct and specific target of miR33. Transfection of macrophages with either miR33 mimics or anti-miR33 in vitro resulted in a decrease or increase of Pgc1α mRNA and protein respectively. Using the Seahorse XF Flux Analyzer, we showed that anti-miR33 treatment boosted maximal mitochondrial oxygen consumption rate, confirming that anti-miR33 impacts positively on mitochondrial respiration. Anti-miR33 treated macrophages also increased the expression of known functional mitochondrial genes (e.g. Slc25a25, Nrf1, Bid and Mtch2), implying miR33 controls several genes in the mitochondrial metabolic pathway. Inhibition of miR33 in vivo in Ldlr-/- mice upregulated Pgc1α mRNA expression in adipose tissue, liver and macrophages. Adipose tissue from anti-miR33 treated obese mice also showed upregulation of so-called “browning” genes (e.g. Ucp-1, Elovl3) that contribute to increased energy utilization of white adipose tissue, possibly improving whole-body metabolism.

Conclusion:
Anti-miR33 therapy specifically targets PGC1α in macrophages and adipose tissue and improves mitochondrial function, all of which can positively regulate inflammatory and energy utilization processes in cardiometabolic diseases (eg. atherosclerosis and obesity).
Abstract 18686: Serial Two Dimensional Echocardiographic Observations and Measurements Obtained by Fetal Echocardiograms: Correlation With Gestational Age
Authors: Gu Xiaoyan , He Yihua , Zhang Ye , Chen Jiancheng , Zhao Ying , Liu Xiaowei , Guo Yong , Chen Jiaoyang , Guo Zhongshan , Li Zhian
Published: April 2024

Objective:
The purpose of the study was to establish changes that may occur between 20 and 34 weeks of pregnancy in linear measurements of the cardiac chambers, great vessels, aortic isthmus, descending aorta and foramen ovale by fetal echocardiography (FE). Regression analysis was utilized to determine any possible correlation between the linear measurements and gestational age.

Methods:
Serial FEs were obtained on 2573 normal single pregnancies with accurate gestational ages. FEs obtained using ASE guidelines were divided into 15 groups according to gestational age.

Results:
Measurements of thoracic diameter, total cardiac diameter, left atrial (LA) and right atrial (RA) diameters, left ventricular (LV) and right ventricular (RV) diameters, and aortic and pulmonary artery diameters significantly increased between 22 and 28 weeks (p < 0.01). Aortic arch isthmus (AoAI), descending Ao diameter, left and right pulmonary artery (PA) diameters and foramen ovale diameter did not change significantly. Between 20 and 34 weeks of pregnancy, RA and RV diameters were always greater than LA and LV diameters, the PA diameter was always greater than Ao diameter, and the AoAI diameter was always greater than the ductal artery (p < 0.01). The ductal artery diameter was always greater than left and right PA Regression analysis between FE dimensions and gestational age showed a significant progressive increase in thoracic and total cardiac diameters, LA and RA diameters, LV and RV diameters, AoAI and descending Ao diameters and ductal artery diameter.

Conclusion:
FE can accurately assess cardiac structure and is capable of establishing normal reference values of cardiac and great vessel anatomy. As expected, most measurements statistically increase with increasing gestational age.
Abstract 18691: Stimulation of Glucagon-Like-Peptide-1 Receptor Through Exendin-4 Preserves Myocardial Performance and Prevents Cardiac Remodeling in Infarcted Myocardium
Authors: DeNicola Megan , Zhao Ting C
Published: April 2024

Background:
We have demonstrated that perfusion of GLP-1 improved myocardial functional recovery in acute myocardial ischemic injury. However, it remains unknown whether stimulation of GLP-1 receptor with exendin-4, a selective GLP-1R agonist, could initiate a protective effect in the heart. Objective: We sought to examine whether stimulation of GLP-1R would produce cardioprotection in post chronic myocardial infarction.

Methods:
Mouse myocardial infarction (MI) was created by ligation of the left descending artery. After 48 hrs, animals were divided into following groups: 1) MI (n=5): animals that underwent MI and received a daily of intraperitoneal injection (i.p.) saline injection as control; 2) MI + exendin-4 (n=5); infarcted mice received injection of exendin-4 (0.1mg/kg). Two weeks later, ventricular function was measured and cardiac hypertrophy were analyzed.

Results:
As compared to control MI hearts, in vivo stimulation of GLP-1R increased the restoration of myocardial functional recovery following MI, which was associated with the prevention of myocardial hypertrophy. GLP-1R stimulation improved the coronary effluent in post-MI hearts. Furthermore, using the in vitro established H9c2 cardiomyoblasts exposed to reactive oxidant species stimulus, we preconditioned H9c2 cardiomyoblasts with exendin-4 at a dose of 100 nmol/L for 1 hr, and they were then subjected to 2 hr of superoxide exposure. In vitro experiments show that the treatment of H9c2 with exendin-4 dramatically decreased the leakage of lactate dehydrogenase (LDH) and increased cell survival, which was also associated with the reduction of apoptosis.

Conclusion:
Our results indicate that GLP-1R serves as a novel approach to eliciting cardioprotection in infarcted hearts and preventing myocardial remodeling.
Abstract 18726: Thrombin-Inhibiting Nanoparticles Prevent Growth of Fibrin Clots by Inhibiting and Adhering to Clot-Bound Thrombin
Authors: Myerson Jacob W , Palekar Rohun U , Wickline Samuel A
Published: April 2024

Introduction:
Sustained and localized prevention of clotting via thrombin inhibition could provide efficient care without significant bleeding effects for clinical scenarios including angioplasty, myocardial infarction, microangiopathy, and acute kidney injury. Thrombin-inhibiting perfluorocarbon nanoparticles (PFC NPs) carrying the direct inhibitors bivalirudin (BVR) and PPACK have demonstrated minimal bleeding effects with inhibition of and binding at sites of acute thrombosis in mouse and rabbit models. Here, we demonstrate that thrombin-inhibiting PFC NPs inhibit clot-bound thrombin and seal clots against further growth when exposed to plasma.

Methods and Results:
In solution, BVR, PPACK, BVR NPs, and PPACK NPs demonstrated concentration-dependent inhibition of Fibrinopeptide A (FPA) production by thrombin, as evaluated by ELISA. FPA ELISA for human plasma exposed to human fibrin clots demonstrated that BVR, PPACK, BVR NPs, and PPACK NPs inhibited thrombin bound in fibrin clots to the same extent as in solution.

Fibrin clots were incubated with non-targeted NPs, BVR NPs, or PPACK NPs. 19F MRI at 12T demonstrated that BVR and PPACK NPs specifically bind to clots (figure 1A).

Clots treated with BVR, PPACK, BVR NPs, PPACK NPs, or saline, were submerged in human plasma and imaged sequentially over one hour in T2-weighted 1H MRI at 12T. Clots treated with saline, BVR, or PPACK grew in volume when exposed to plasma, adding loose fibrin gel. Clots treated with BVR or PPACK NPs did not grow significantly (figure 1B-E).

Conclusions:
Thrombin-inhibiting PFC NPs have previously been shown to specifically bind to sites of acute thrombotic injury. Data presented herein show that PPACK and BVR NPs inhibit activity of clot-bound thrombin and specifically bind to fibrin clots derived from human plasma. PPACK and BVR NPs bound on the surface of fibrin clots prevent further clot growth on exposure to plasma.
Abstract 18733: Evaluation of a Super-Sensitivity Cardiac Troponin I Assay for Diagnosing Non ST-Segment Elevation Myocardial Infarction
Authors: Schofer Niklas , Brunner Fabian , Schlueter Michael , Francisco Ojeda , Zeller Tanja , Baldus Stephan , Bickel Christoph , Lackner Karl , MÜnzel Thomas , Keller Till , Blankenberg Stefan , Goldmann Britta
Published: April 2024

Introduction:
Acute myocardial infarction (AMI) is defined by cardiac troponin (cTn) elevation. According to current guidelines the diagnosis of AMI requires a rise or fall of cTn (delta) with at least one value above the diagnostic cutoff, i.e. the 99th percentile (P99) of a reference population. Lately, cTn assays with high analytical precision have become available. Use of high-sensitivity cTn showed improved diagnostic accuracy with absolute deltas being superior compared to relative deltas. The diagnostic utility of super-sensitivity cTn assays, that are capable of cTn detection in >95% of the general population, has not been sufficiently elucidated.

Hypothesis:
We assessed the hypothesis that a super-sensitivity cTnI assay combined with a diagnostic algorithm that incorporates an absolute delta provides sufficient detection of non ST-segment elevation myocardial infarction (NSTEMI).

Methods:
The study comprised 1566 patients with new-onset chest pain (246 with NSTEMI, 222 with unstable angina pectoris, 1097 with non-coronary chest pain). On admission and 3 hours later cTnI was measured by a super-sensitivity assay (Erenna® cTnI immunoassay, Singulex, Inc., Alameda, CA, USA). Diagnostic performance was assessed via a two-step algorithm: First, 3h-cTnI had to exceed a certain cutoff concentration (P99 as well as arbitrarily chosen cTnI concentrations) and, when this criterion was fulfilled, secondly, an absolute delta criterion was applied.

Results:
A 3h-cTnI cutoff concentration of 40 ng/l provided a negative predictive value of 99.1% and a sensitivity of 95.5% indicating confident rule-out of NSTEMI, when this criterion was not fulfilled (n=1256). For patients with 3h-cTnI >40 ng/l (n=310) an absolute delta of ≥50 ng/l resulted in a positive predictive value, i.e. diagnostic certainty for ruling in NSTEMI, of 84.2%. Application of this algorithm to the overall study population yielded a negative predictive value of 96.1%, positive predictive value of 84.2%, sensitivity of 81.8% and a specificity of 97.1%.

Conclusion:
In conclusion, the super-sensitivity cTnI assay showed a clinically acceptable performance in diagnosing NSTEMI by use of an algorithm that is P99-independent and includes an absolute delta.
Abstract 18735: Worsening Right Ventricular Structural Mechanics in Constrictive Pericarditis; Pericardiectomy Didn’t Fix the Problem!
Authors: Tariq Muhammad U , Alraies M C , Kusunose Kenya , Klein Allan
Published: April 2024

Introduction:
Constrictive pericarditis (CP) is the result of scarring and consequent loss of the normal elasticity of the pericardial sac. Pericardiectomy is the definitive treatment for most cases of constriction. However it is believed structural changes in the right ventricle (RV) may result in tricuspid regurgitation (TR) after total pericardiectomy in patients with CP.

Case report This is the case of a 55-year-old man who had a history of viral pericarditis, HTN and heart failure. He was evaluated for progressive pedal edema and ascites, found to have CP with equalization of RV and LV diastolic pressures and respiratory discordance of systolic pressures, consistent with CP on right heart catheterization. He underwent pericardiectomy and was found to have extensive pericardial adhesions and severe calcifications. Seven weeks later, he presented with complaints of fluid overload and was noted to have newly decreased RV systolic function accompanied by increase in RV volume with tricuspid annular dilation and 2-3+TR (Table and Figure). Diuretics were reinitiated and he is followed for potential tricuspid valve surgery.

Discussion TR may develop post pericardiectomy in patients with CP. This is commonly noted with persistent RV failure symptoms post operatively. It may be caused by RV dilation and worsening TR, which results in increased RV strain, signifying poor status of longitudinal RV function. Tricuspid regurgitation is explained by RV and tricuspid annular dilatation. It is important to have a detailed evaluation perioperatively in patients with CP undergoing pericardiectomy.
Abstract 18738: Pulmonary Artery Systolic Pressures Increase With Aging: A Longitudinal, Population Based Study
Authors: Chandra Suparna M , Redfield Margaret M , Karon Barry L , Rodeheffer Richard J , Kane Garvan C
Published: April 2024

Background:
A community based, cross-sectional echo survey demonstrated that pulmonary artery systolic pressure (PASP) increases with age and that PASP is associated with systemic arterial stiffness, Doppler estimated left ventricular (LV) filling pressures and lung function. Longitudinal assessment of PASP is needed to confirm cross-sectional observations.

Objectives:
To assess the whether PASP changes over time in longitudinally studied subjects and determine whether changes in PASP are associated with changes in systemic vascular stiffness, LV filling pressures or lung function.

Methods:
A random sample (n=2042) of the Olmsted County, MN population over age 40 underwent echo, record review and spirometry between 1997-2000 (Exam 1). A subset (n=1402) underwent repeat studies four years later (2001-2004; Exam 2). The current analysis includes the 723 subjects with paired PASP measurements. Changes ([[Unable to Display Character: ▵]]) in PASP, systemic arterial stiffness (pulse pressure; PP), LV filling pressure (E/e’) and lung function (% age/sex expected forced expiratory volume, %FEV1) were assessed.

Results:
At Exam 1, the median (interquartile range) age was 62 (69-70) years (62% female). Median time between exams was 48 (47-49) months. PASP increased from 26.1 (24.4-30.0) mmHg at Exam 1 to 28.0 (24.4-32.0) mmHg at Exam 2 (p<0.0001 by paired t test) for an average (SD) [[Unable to Display Character: ▵]] of 1.2 ± 5.5 mmHg. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] age with an increase (parameter estimate (pe) ± standard error (se)) of 1.4±0.7 mmHg per year increase in age (p=0.046). [[Unable to Display Character: ▵]]PASP was not associated with sex and there was no age-sex interaction. Adjusting for age and PASP at Exam 1, [[Unable to Display Character: ▵]] age and Exam 1 values for PP, E/e or %FEV1 as appropriate, [[Unable to Display Character: ▵]]PASP was associated with [[Unable to Display Character: ▵]] PP (pe±se = 0.03±0.01 mmHg; p=0.01) [[Unable to Display Character: ▵]]E/e’ (pe±se = 0.21±0.06 mmHg, p=0.001) and [[Unable to Display Character: ▵]]%FEV1 (-0.09±0.02 mmHg, p<0.0001) suggesting that increases in PASP were related to increases in vascular stiffening, increases in LV filling pressures and declining lung function.

Conclusions:
In this longitudinal, population based study we find that PASP increases with aging and that increases in PASP over time are related to increases in systemic vascular stiffness and LV filling pressures and decreases in lung function.
Abstract 18748: High Resolution Structure Determination and Small Molecule Inhibitor Identification of NPP4, a Procoagulant Enzyme Localized to Brain Vascular Endothelium
Authors: Braddock Demetrios
Published: April 2024

We recently identified the enzyme NPP4, an uncharacterized member of the nucleotide pyrophosphatase/phosphodiesterase family, as present at high concentrations on the vascular surface of the brain and promotes platelet aggregation in a dose dependent manner at physiologic concentrations of AP3A. AP3A is a small molecule stored at high concentrations in platelet dense core granules and is released upon platelet activation at high concentrations in the vicinity of the growing thrombus. Ap3A has a significantly longer lifespan in whole blood than ADP and has long been thought to promote stable thrombus formation by serving as a ‘chemically masked’ source of ADP. The goal of the present study was to determine the high-resolution three-dimensional structure of NPP4, and to identify small molecule inhibitors of NPP4 useful for the in vitro and in vivo validation of the physiologic role of the enzyme. We used X-ray crystallography to determine the high-resolution structure of the enzyme, and high-throughput small molecule screening to identify lead small molecules as lead inhibitors.

The three-dimensional structure of the enzyme was determined to1.5Å resolution in the presence and absence of its enzymatic product (AMP), and high-affinity (nM) small molecule inhibitors of NPP4 were identified as lead inhibitors in high throughput small molecule screens. Structure-activity relationships (SAR) of the lead compound were explored via chemical derivatization, and three-dimensional structures of the lead compounds were obtained to assist a structure-guided approach to lead optimization. Our combined studies lay the foundation for the validation of the biological role of NPP4 in hemostasis and establishes the necessary tools and reagents for the translational application of our preliminary findings into the clinic.
Abstract 18762: The Association Between Atrial Fibrillation and Sudden Cardiac Death is Confounded by Clinical History of Congestive Heart Failure
Authors: Reinier Kyndaron , Marijon Eloi , Uy-Evanado Audrey , Teodorescu Carmen , Chugh Harpriya , Gunson Karen , Jui Jonathan , Chugh Sumeet S
Published: April 2024

Introduction:
Atrial fibrillation / flutter (AF) has been associated with overall cardiac mortality, and recent studies have reported an association with sudden cardiac death (SCD). Since AF and SCD share many of the same risk factors, we hypothesized that this association could potentially be explained by other clinical predictors, especially a clinical diagnosis of congestive heart failure (CHF).

Methods:
In an ongoing prospective case-control study of SCD in a metro region of the Northwestern US (pop. approx. 1 million), cases of SCD were ascertained from the region’s EMS system, medical examiner, and hospitals and adjudicated by systematic review of arrest circumstances and medical records. SCD cases age ≥18 (2002-2012) with physician records and a cardiac evaluation by ECG or echocardiogram were compared to control subjects with coronary artery disease (CAD) from the same geographic region. AF was defined by physician-documented medical history or from a pre-arrest ECG or echocardiogram.

Results:
Case subjects (n=935, age 71 ± 13 yrs, 64% male) were more likely than control subjects (n=679, age 66 ± 12 yrs, 66% male) to have a history of myocardial infarction (41% vs. 34%, p=0.004), CHF) (45% vs. 18%, p<0.0001), cerebrovascular accident (CVA) (22% vs. 10%, p<0.0001), and diabetes (41% vs. 32%, p=0.0004), but less likely to have documented hyperlipidemia (54% vs. 82%, p<0.0001). Among all subjects, cases were significantly more likely to have a history of AF than controls (29% vs. 18%, p<0.0001). However, AF was strongly associated with a history of CHF: AF was prevalent in 44% of subjects with CHF and 15% of subjects without CHF (p<0.0001). In multivariable models, AF was significantly associated with SCD when adjusting for age, gender, history of MI, hypertension, CVA, diabetes, and dyslipidemia (p=0.01), but when CHF was added to the model, the AF-SCD association was no longer significant (OR 1.05, 95% CI 0.8 - 1.4, p=0.74). In this model, CHF remained a significant predictor of SCD risk (OR 3.5, 95% CI 2.6 - 4.5).

Conclusions:
In this population-based study, the AF-SCD association appears to be driven by a clinical history of CHF. These findings have potential implications for clinical and mechanistic approaches to AF and SCD.
Abstract 18772: Impact of Hematoma After Pacemaker Implantation: An Analysis of a Nationwide Database of 77,074 Patients
Authors: Mahankali Sridhar Arun Raghav , Reddy Madhu , Vallakati Ajay , Maybrook Ryan , Berenbom Loren , Dawn Buddhadeb , Lakkireddy Dhanunjaya
Published: April 2024

Introduction:
Pocket hematoma is one of the most common complications associated with pacemaker implantation. We sought to identify the incidence of pocket hematoma after a de novo pacemaker implantation and evaluate its impact on the hospital outcomes using a large all-payer national inpatient database.

Methods:
Data from Nationwide Inpatient Sample 2010 was used to identify all hospitalizations for a pacemaker implantation. All primary implantations of single chamber, dual chamber and biventricular pacemakers during the year 2010 were identified using the appropriate ICD-9 codes. We then identified the patients who experienced a procedure related hematoma during the hospital stay. We then compared the outcomes of the patients with and without a hematoma complication. All analyses were performed using SPSS 20 complex samples using appropriate weights to adjust for the complex sampling design of the national database.

Results:
Out of a total of 77,074 primary pacemaker implantations in the year 2010, 1677 (2.1%) of the implantations were complicated by a hematoma. Patients with biventricular pacemakers were more likely to develop a hematoma than single or dual chamber pacemakers (2.7% vs 1.5%; p<0.001). No other demographic variables or hospital categories were associated with a hematoma formation. Patients who developed a hematoma had a higher mortality (2.0% vs 0.7%, p<0.001), longer hospital length of stay (8.7 days vs 4.8 days, p<0.001) and higher in-hospital charges ($155,071 vs $108,225, p<0.001) compared to patients who did not develop a hematoma. The adverse outcomes associated with hematoma were noted with all the pacemaker sub-types.

Conclusions:
Hematoma is an uncommon complication associated with pacemaker implantation and adversely impacts in-hospital outcomes.
Abstract 18775: Longterm Follow-Up After Surgical Ablation Therapy for Atrial Fibrillation Using an Implantable Cardiac Rhythm Monitoring Device
Authors: Kowert Anke , Reichart Bruno , Juchem Gerd
Published: April 2024

Objectives:
After ablation, intermittent and symptom-based monitoring of the heart rhythm may not be reliable in identifying patients with ongoing atrial fibrillation (AF). For accuracy of rhythm surveillance after surgical ablation leadless implantable cardiac rhythm monitoring devices (ICM) were implanted.

Methods:
Surgically ablation of AF was accomplished following the Cox-Maze technique modified after Damiano. Lines were produced with bipolar radiofrequency using the AtriCure
®
clamp. Continuity near the AV-valves was achieved applying the unipolar Isolator
®
Pen. In each case concomitant cardiovascular procedures were necessary. At the end of the interventions the ICMs were implanted. Amiodaron was given for six and phenprocoumon for twelve postoperative months. Patient follow-up was conducted by means of transtelephonic transmission on a monthly basis. The attending physician in private practice got access to the remote monitoring.

Results:
A group of 27 patients were continuously monitored over a period of three years. Preoperatively, 15% of the patients had paroxysmal, 59% persistent and 26% permanent AF. Mean postoperative AF burden as indicated by ICM declined continuously over twelve months: From 35 to 7% (preoperative paroxysmal), 60 to 25% (preoperative persistent) and 83 to 64% (preoperative permanent). ). The treatment is less effective for patients with permanent AF and severe heart failure. Atrial flutter was detected in two patients. Symptomatic bradycardia necessitated two permanent pacemakers.

Conclusion:
Continuous heart rhythm monitoring with an ICM detected AF burden higher then expected. The duration of AF decreases significantly in the course of the first year only. After this period of time, anticoagulation could be reconsidered. Intensified heart rhythm follow-up and local medical networking can improve cardiac therapy.
Abstract 18790: Therapeutic Efficacy of Cardiosphere-Derived Cells in a Transgenic Mouse Model of Nonischemic Dilated Cardiomyopathy
Authors: Aminzadeh Mohammad A , Tseliou Eleni , Sun Baiming , Cheng Ke , Malliaras Konstantinos , Makkar Raj R , Marbán Eduardo
Published: April 2024

Introduction:
Cardiosphere-derived cells (CDCs) produce regenerative effects and improve function in the post-infarct setting. However, it is unclear whether CDCs are beneficial in non-ischemic dilated cardiomyopathy (DCM). We tested the effects of CDC transplantation in mice with cardiac-specific Gαq overexpression, which leads to intense myocardial oxidative/nitrosative stress and inflammation. These mice predictably develop progressive cardiac dilation and failure, with accelerated mortality.

Methods and Results:
A total of 71 mice were investigated in this study. Wild-type syngeneic mouse CDCs (10
5
cells total) or vehicle only were injected intramyocardially at five left ventricular sites in 6-, 8- and 11-week old Gαq mice. Cardiac function deteriorated in vehicle-treated mice over 3 months of follow-up, accompanied by oxidative stress, inflammation and adverse ventricular remodeling. Left ventricular (LV) ejection fraction and LV end-diastolic and end-systolic volumes were progressively worsened over 3 months observational period in vehicle-treated mice compared to CDC-treated group (p<0.05). This was associated with upregulation of reactive oxygen species- and nitric oxide-producing enzymes [NAD(P)H oxidase and inducible nitric oxide synthase], accumulation of proinflammatory oxidant product, 3-Nitrotyrosine, intense infiltration of inflammatory cells [CD68
+
macrophages and CD3
+
T cells], increased apoptosis and activation of pathologic remodeling pathway, PKC-PKD-CREB. Concomitantly, marked collagen I and III deposition and fibrosis were observed in the vehicle-treated Gαq mouse heart. In contrast, CDCs preserved cardiac function and volumes (p<0.05), and promoted cardiomyocyte cycling (p<0.01) while blunting Gαq-induced oxidative stress, inflammation and fibrosis in the heart. Survival was enhanced by CDCs (p<0.005) in Gαq mice that had been subjected to doxoribicin stress.

Conclusions:
CDCs reverse fundamental abnormalities in cell signaling, prevent adverse remodeling and improve survival in a mouse model of DCM. These findings motivate testing of CDCs as a potential therapeutic to prevent disease progression in patients with early-stage DCM.
Abstract 18792: Treatment With an EET Agonist in a Post Myocardial Infarction Model Increases Left Ventricular Ejection Fraction and Attenuates Cardiac Remodeling by Induction of HMOX1
Authors: Cao Jian , Thompson Ellen , Abraham Nader G , Peterson Stephen J , Zeldin Darryl C , Schwartzman Michal L
Published: April 2024

Rationale:
Myocardial Infarction (MI) leads to a progressive decline in cardiac function, an increase in patient morbidity and is an event expanding burden on the health care system. Failure of myocardial regeneration, insufficient blood flow and enhanced oxidative stress all contribute to this pathological outcome.

Objective:
Since epoxyeicosatrienoic acids (EETs) agonists increase angiogenesis and vasodilation in ischemic heart, we examined if cross talk between EET and heme oxygenase-1(HMOX1) could reduce post infarcted cardiac remodeling resulting in an improvement of cardiac function in a model of post-MI.

Methods:
C57B16 mice were divided into 4 groups: sham, mice with myocardial infarction (MI) via LAD ligation and mice with MI treated with an EET-agonist (NUDSA) with and without the HO activity inhibitor stannous mesoporphyrin (SnMP). NUDSA was administered 5 days after MI for 30 days (0.5 mg/kg). Myocardial echocardiography was performed to assess blood volume, velocity, LVend-diastolic and ejection fractions. Microvessel density, inflammation and pericardial fibrosis were compared among the groups.

Results:
Echocardiography showed that left ventricle dilatation, measured as end diastolic area (EDA), was reduced in the NUDSA treated group compared to the MI group (EDA: MI: 0.314 ±0.01 cm
2
; MI+NUDSA: 0.193±0.02 cm
2
; p<0.01). Cardiac Index, decreased by MI, was restored by NUDSA. NUDSA treatment increased serum adiponectin levels and decreased IL-6 and MCP-1 levels (p<0.05 vs. MI), reduced fibrosis in the peri-infarct myocardium and decreased apoptosis. Immunoblot analysis of cardiac tissue demonstrated increased expression of HMOX1, VEGF and FGF along with decreased expression of TXA2 and 3NT in mice treated with NUDSA as compared to the MI group (p<0.02). All these beneficial effects were reversed by SnMP.

Conclusion:
This study demonstrates that cross talk between EET and HMOX1 ameliorates cardiac remodeling in the post infarcted myocardium and increases angiogenesis, suggesting EET as a potential therapeutic strategy in the preservation of cardiac function in this animal model of post MI.