bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18171: Post-Exercise T-Wave Alternans as a Predictor of Fatal and Non-Fatal Cardiovascular Events
Authors: Kenttä Tuomas , Perkiömäki Juha S , Junttila M J , Piira Olli-Pekka , Lepojärvi Samuli , Huikuri Heikki V
Published: April 2024

Purpose:
T-wave alternans (TWA), a measure of beat-to-beat fluctuations in the ventricular repolarization, has been proposed to reflect the vulnerability to arrhythmic death in various populations. We tested the hypothesis that the presence of TWA may also predict non-arrhythmic cardiac events, such as heart failure and vascular events.

Methods:
Exercise electrocardiograms of 1017 patients with angiographically documented stable coronary artery disease (CAD) were analyzed for TWA with the modified moving average (MMA) method. End-points of the study were cardiac death, hospitalization due to heart failure, acute coronary event and stroke.

Results:
During a two-year follow-up, 21 patients experience cardiac death, 24 patients were hospitalized due to heart failure, 104 had acute coronary event, and 54 had stroke/transient ischemic event (TIA). TWA ≥ 23.5 μV during post-exercise recovery was predictive of cardiac death (hazard ratio [HR]: 6.72, 95% confidence interval [CI]: 1.93 - 23.37, P=0.003), but it did not predict hospitalization for heart failure (HR: 1.78, 95% CI: 0.74 - 4.29, P=0.201), occurrence of acute coronary event (HR: 1.06, 95% CI: 0.71 - 1.58, P=0.783), or stroke/TIA (HR: 1.16, 95% CI: 0.66 - 2.04, P=0.597). When adjusted with age, gender, diabetes, left ventricular ejection fraction (LVEF), maximum heart rate and baseline systolic blood pressure, maximum post-exercise TWA remained predictive of cardiac death with a multivariate hazard ratio of 5.28 (95% CI: 1.49 - 18.69, P=0.010).

Conclusions:
Post-exercise TWA is especifically associated with an increased risk of short-term fatal cardiac events in patients with stable CAD, but it is not a strong predictor of non-fatal cardiac events
Abstract 18175: Cytoglobin-Defiencient Mice Develop Maladaptive Cardiac Remodeling After Ischemia-Reperfusion Injury Due to Alterations in NF-kB Signaling
Authors: Canseco Diana C , Von Grote Erika , Singh Sarvjeet , Rothermel Beverly A , Mammen Pradeep P
Published: April 2024

Cytoglobin (
Cygb
) is a stress-responsive hemoprotein expressed in cardiomyocytes. Data from our laboratory indicate
Cygb
is able to translocate to the nucleus under stress and one mechanism by which it is able to exert its cytoprotective effect is by serving as a repressor of p53 transcriptional activity. In a model of ischemia-reperfusion (IR),
Cygb
transcript levels within wild-type hearts peak 2 days post-IR injury. We hypothesize that
Cygb
modulates cardiac remodeling following IR injury by effecting redox sensitive signaling pathyways (p53, NF-κB, etc). To test our hypothesis, we generated mice with cardiac-specific deletion of
Cygb
(
Cygb+/-
). These mice are viable with normal cardiac function under baseline conditions [ECHO: FS(%) 70±0.05 vs 72±0.05,
Cygb+/-
vs control (Ctrl); p=NS, n=12]. However,
Cygb+/-
mice develop worse cardiac remodeling 1 month post-IR injury [FS(%) 35±0.05 vs 59±0.05, p<0.005, n=8; %Fibrosis of LV 40 vs 20, p<0.05, n=4;
Cygb+/-
vs Ctrl] with evidence of increased cardiomyocyte cell death (TUNEL 8.0±0.5 vs 2.0±0.5 cells per unit area,
Cygb+/-
vs Ctrl; p<0.05, n=4).
In vitro
assays utilizing small interference RNA targeting Cygb also support the importance of
Cygb
in maintaining cardiomyocyte viability under hypoxic conditions (%Viability 47.34±0.05 vs 57.14±0.05, hypoxic si
Cygb
H9C2 vs hypoxic Ctrl siRNA H9C2 cells; p<0.05, n=6). A transcriptome analysis of the NF-κB signaling pathway (60 genes including IL-6, Myd88, CSF2, and TLR3) revealed a global downregulation in expression of NF-κB target genes in hypoxic H9C2 cells and IR-injured
Cygb+/-
hearts. Utilizing
in vitro
assays (Luc assays, etc) NF-κB activity in si
Cygb
H9C2 cells was decreased in a p53-dependent manner. This data was confirmed by demonstrating decreased NF-κB activity in 2 day post-IR injured
Cygb
+/- hearts. Collectively, our data suggests
Cygb
modulates cardiac remodeling post-IR injury by affecting NF-κB signaling via a p53-dependent mechanism.
Abstract 18181: Real-Time Non-ECG-Gated First-Pass Perfusion MRI Enabling Concurrent Assessment of Myocardial Function and Perfusion Abnormalities
Authors: Sharif Behzad , Arsanjani Reza , Dharmakumar Rohan , Shalev Aryeh , Thomson Louise , Bairey Merz Noel , Berman Daniel S , Li Debiao
Published: April 2024

Introduction:
Combined assessment of wall motion and perfusion abnormalities from cardiac MRI (CMRI) has been shown to have a high performance for diagnosis of coronary artery disease (CAD). CMRI acquisition, however, is hindered by study length, presence of arrhythmias, and the need for synchronization with cardiac cycle via ECG gating. We developed a new non-ECG-gated CMRI technique capable of simultaneously capturing perfusion and wall motion abnormalities in a single 1-minute scan.

Hypothesis:
Real-time (non-ECG-gated) CMRI can detect perfusion abnormalities with high image quality and enables assessment of wall motion from the same data.

Methods:
A novel real-time MRI method was developed for ungated first-pass perfusion (FPP) imaging (continuous T1-weighted scan). Canines (n=5) with reversible ischemia (severe LAD stenosis) were studied using both the real-time and gated (conventional) methods. Six normal subjects and 1 patient (suspected CAD) had stress/rest real-time FFP CMRI. The patient also underwent Rb-82 stress/rest myocardial perfusion PET.

Results:
The real-time FPP stress/rest human studies were all of high quality. The 6 normal subjects demonstrated normal perfusion and function. In the patient, stress-induced hypoperfusion was observed, corresponding to a reversible defect on PET (Figure). In animals, real-time FPP achieved high contrast-to-noise ratio between hypoperfused/remote territories (real-time: 5.2, gated: 4.8). Wall thickening abnormalities (17 frames/s) were observed in hypoperfused areas.

Conclusions:
A novel approach to FPP CMRI has been developed that does not use ECG gating. Preliminary results in animals with ischemia and at stress/rest in humans were of high quality and showed expected perfusion findings. The real-time method is an attractive alternative to conventional CMRI with the advantage of simplicity (no gating), speed (concurrent MRI of function and perfusion), and potentially improved reliability.
Abstract 18182: Intra-Aortic Balloon Pump Improves Right Ventricular Function in Patients with End-Stage Congestive Heart Failure
Authors: Kapelios Chris , Terrovitis Ioannis , Ntalianis Argyrios , Kaldara Elisabeth , Repasos Evaggelos , Siskas Panagiotis , Kontogiannis Chris , Sousonis Vassilis , Sfakianaki Titika , Charitos Chris , Alexopoulos George , Nanas John
Published: April 2024

Objective:
Right ventricular dysfunction is a major contraindication for implantation of left ventricular assist device (LVAD) in patients with end stage heart failure (HF). The objective of the study was to investigate the effect of prolonged IABP support on anatomy and function of right ventricle (RV) in patients with idiopathic dilated cardiomyopathy (IDM) and end-stage HF.

Methods:
We recorded the baseline characteristics and the course of the echocardiography indices of right ventricular function in patients with IDM and HF ineligible for LVAD implantation who underwent support with IABP as bridge to candidacy in our hospital between May 2009 and Nov 2012.

Results:
During this period, 15 patients (mean age 49.3 ± 14.2 years) underwent support with IABP for a mean period of 91.1 ± 55.1 days [range 21-215 days]. All patients suffered from IDM and were severely symptomatic (New York Heart Association class IV). Nine patients (60%) were in INTERMACS level II while the other six were in INTERMACS level 1. Mean left ventricular ejection fraction, pulmonary capillary wedge pressure, cardiac index, BNP, and daily furosemide dose were 21.6 ± 7.3%, 24.8 ± 6.0 mmHg, 1.43 ± 0.33 L/min/m
2
, 2468 ± 1201 pg/ml και 801 ± 608 mg. The support with IABP led to reduction of right ventricular dimensions (RV base from 42.4 ± 2.3 to 37.7 ± 7.9 mm, p=0.24, mid RV from 33.7 ± 5.7 to 27.4 ± 7.2 mm, p=0,001) and to amelioration of systolic function (max velocity of the tricuspid annulus [Sm] from 9.1 ± 1.9 cm/s to 11.3 ± 2.1 cm/s, p=0.006). Right ventricular stroke work index (RVSWI), a valuable marker of intra-operative mortality demonstrated significant increase (from 352.6 ± 217.3 to 557.5 ± 136.2 mmHg x ml/m
2
, p=0.022). Even IVA, an indice which reflects RV myocardial contractility , largely independent of loading conditions also increased with IABP support (from 0.76 ± 0.35 m/s
2
to 1.43 ± 0.69 m/s
2
, p=0.043, [Normal values: 1.4 ± 0.5 m/s
2
]).

Conclusion:
Support with IABP of end stage HF patients with dilated cardiomyopathy improves RV function, potentially rendering patients previously ineligible for LVAD to candidates for this life saving treatment.
Abstract 18185: Regression of Severe Left Ventricular Hypertrophy After Transcatheter Valve Replacement for Aortic Stenosis: Impact on Clinical Outcomes in PARTNER Cohort A
Authors: Lindman Brian R , Stewart William , Pibarot Philippe , Hahn Rebecca T , Weissman Neil J , McAndrew Thomas C , Szeto Wilson Y , Makkar Raj , Miller D. Craig , Babaliaros Vasilis , Kapadia Samir , Bowers Bruce , Greason Kevin L , Leon Martin B , Sarano Maurice , Devereux Richard B , Otto Catherine M , Douglas Pamela S
Published: April 2024

Background:
Left ventricular (LV) mass regression after aortic valve replacement (AVR) for aortic stenosis (AS) is a favorable effect of LV unloading, but its relationship to improved clinical outcomes is unclear. We examined the effect on clinical outcomes after transcatheter AVR (TAVR) of: 1) amount of LV mass index (LVMi) regression; and 2) persistent severe LV hypertrophy (LVH).

Methods:
Of 2115 patients with symptomatic AS at high surgical risk receiving TAVR in the PARTNER randomized trial or continued access registry, 462 (55% women) who had severe LVH (LVMi ≥149 g/m
2
men, ≥122 g/m
2
women, by ASE criteria) at baseline (BL) and LVMi measured 6 mo post-TAVR were included in our analysis. The effect of LVMi regression was evaluated by comparing outcomes in patients with greater vs. lesser decrease (dichotomized by median % change) in LVMi between BL and 6 mo, and in those without vs. with persistent severe LVH 6 mo post-TAVR. Cox PH models evaluated rates of all-cause mortality (6-12 mo), rehospitalizations (through 1 yr), and the composite of these two outcomes.

Results:
LVMi decreased from 173±32 (BL) to 121±25 g/m
2
(6 mo) (p<0.001) in those with greater LVMi regression, and from 164±30 (BL) to 158±34 g/m
2
(6 mo) (p<0.001) in those with lesser LVMi regression. Patients with greater vs. lesser LVMi regression had similar baseline clinical characteristics, a lower rate of rehospitalization (10.5% vs. 19.9%, p=0.006) and lower rate of the composite endpoint of death or rehospitalization (13.2% vs. 21.4%, p=0.02), but a similar rate of death (4.9% vs. 4.8%, p=0.86). Persistent severe LVH at 6 mo post-TAVR was present in 54% (58% of whom were women). Patients without vs. with persistent severe LVH had similar baseline clinical characteristics, a lower rate of rehospitalization (11.9% vs. 18.1%, p=0.053) and lower rate of the composite endpoint of death or rehospitalization (13.3% vs. 20.7%, p=0.03), but a similar rate of death (3.9% vs. 5.7%, p=0.42). Similar results were obtained when including patients with moderate or severe LVH.

Conclusions:
In high-risk patients with severe AS and severe LVH undergoing TAVR, greater LV mass regression and resolution of initially severe LVH at 6 months are associated with a lower rate of death or repeat hospitalization.
Abstract 18207: A Prospective, Single Arm Feasibility Study to Evaluate the Safety and Performance of a Novel Embolic Deflection Device in Patients Undergoing Transcatheter Aortic Valve Replacement: Results From the Deflect I Study
Authors: Lansky Alexandra , Baumbach Andreas , Meller Stephanie M , Brickman Adam , Margolis Pauliina , Kovac Jan , Hildick- Smith David , Pietras Cody , Heier Peter D , Voros Szilard , Mullen Michael
Published: April 2024

Background:
Stroke associated with transcatheter aortic valve replacement (TAVR) is primarily due to intra-procedural mechanical embolization of calcific atherosclerotic plaque. Filter-based embolic protection devices may address this devastating complication.

Objectives:
:
The results of the novel TriGard
TM
embolic deflection device used in conjunction with (TAVR) in 20 consecutive patients in the DEFLECT I clinical trial.

Methods:
DEFLECT I is a prospective, multi-center, single arm study designed to demonstrate the safety and performance of the TriGard
TM
Embolic Deflection Device (EDD) (Keystone Heart, Caesarea Business Park, Israel), among patients undergoing TAVR. The EDD is designed to be positioned across all major cerebral arteries in the aortic arch. Primary endpoints were device performance and in-hospital device-related safety. A powered secondary endpoint was the number and volume of new diffusion-weighted magnetic resonance imaging (DW MRI) brain lesions from pre-procedure to 4±2 days post-procedure compared to historic controls.

Results:
:
20 consecutive patients undergoing TAVR were enrolled at 5 sites. All devices were positioned and retrieved successfully. The device performed as intended with complete vessel coverage until completion of the valve implant in 80% of cases. There were no in-hospital EDD-related adverse events. In-hospital procedure-related MACCE was 10% due to major disabling strokes in 2/20 patients occuring the day after the procedure. Compared with historical controls, the number of new ischemic brain lesions detected on DW MRI (70% vs. 76%) were similar; however, patients undergoing TAVR with the EDD demonstrated 94% reductions in the maximum lesion volume (p<0.01) and maximum total lesion volume (p<0.01) and a 65% reduction in mean lesion volume (p<0.01) compared with historical controls.

Conclusions:
The DEFLECT I study demonstrated safety and feasibility of the TriGard
TM
device in patients undergoing TAVR. The TriGard
TM
device significantly reduced the total and maximum volume of cerebral ischemic brain lesions compared to historic controls.This study established proof of concept of the TriGard
TM
device and justifies further evaluation in a planned randomized clinical trial.
Abstract 18229: Vacuolar Protein Sorting-Associated Protein 4A (VPS4A), a Target of miR-16, in Fibroblasts
Authors: Adhikari Neeta , Guan Weihua , Capaldo Brain , Carlson Marjorie , Ramakrishnan Sundaram , Walek Dinesha , Gupta Manu , Mackey Aaron , Barton Paul J , Hall Jennifer L
Published: April 2024

.

Members of the miR-16 family are up-regulated during ischemia and heart failure. The goal of these studies was to identify novel miR-16 mediated signaling pathways that may play a role in cardiovascular disease. We used bioinformatics to identify single nucleotide polymorphisms (SNPs) in binding sites of miR-16 using dbSNP and the exome sequencing project. Target genes with a SNP in a miR-16 binding site included cingulin 1 (
CGNL1
), zinc finger protein with CRAB and SCAN domains 1 (
ZKSCAN1
), uncoupling protein2 (
UCP2
), vacuolar protein sorting- associated protein 4A (
VPS4A
), and a disintegrin and metalloproteinase with a thrombospondin motif 1 (
ADAMTS-1
). The role of
VPS4A
in the heart is not known.
VPS4A
mRNA expression was greater in primary rat cardiac fibroblasts (0.41±0.02) compared to primary rat cardiac myocytes (0.21± 0.03) (n=3-4, p=0.003). Up-regulation of
VPS4A
in HEK 293T cells decreased cell number by 30% and 41% at 48h and 72h, respectively, compared to cells transfected with a control scrambled mimic (n=6, p<0.01). Thus
VPS4A
was further studied for its direct interaction with miR-16. Overexpression of a miR-16 mimic decreased VPS4A protein expression by 38% and 52 % at 48h and 60h, respectively, compared to cells transfected with a control scrambled mimic (n=3, p<0.01). Conversely, inhibiting endogenous miR-16 with a miR-16 inhibitor mimic increased VPS4A protein 1.5 fold (n=3, p<0.01). miR-16 decreased luciferase activity of a
VPS4A
-3’UTR promoter construct; however the presence of rs16958754 in the miR-16 binding site inhibited the interaction (n=10, p<0.01). In sum, we identified
VPS4A
as a novel downstream target of miR-16 in fibroblasts. This data supports a working model in which upregulation of miR-16 with heart failure decreases
VPS4A
, and promotes fibroblast proliferation. Work is underway to determine if the SNP rs16958754 may be protective under certain conditions in which limiting fibroblast proliferation may be beneficial.
Abstract 18232: The Magnitude of Hyperemic Microvascular Resistance Determines the Functional Consequences of Fractional Flow Reserve-Positive Coronary Stenoses, as Well as the Optimal Fractional Flow Reserve Cut-Off Value for Stenosis-Specific Inducible Myocardial Ischemia
Authors: van de Hoef Tim P , Nolte Froukje , van Lavieren Martijn A , Meuwissen Martijn , Chamuleau Steven A , Voskuil Michiel , Henriques José P , Koch Karel T , de Winter Robbert J , Spaan Jos A , Siebes Maria , Tijssen Jan G , Piek Jan J
Published: April 2024

Background:
Although myocardial ischemia is a consequence of both epicardial and microvascular abnormalities, clinical decision-making by fractional flow reserve (FFR) is purportedly based on the extent of epicardial disease only. Nonetheless, FFR is recognized to be sensitive to the magnitude of hyperemic microvascular resistance (HMR), which is not accounted for in FFR-guided diagnostic strategies. We aimed to determine pertinence of hyperemic microvascular resistance for the occurrence of inducible myocardial ischemia in FFR-positive (FFR≤0.80) and FFR-negative (FFR>0.80) lesions, as well as for the optimal FFR cut-off value to identify stenosis-specific inducible myocardial ischemia.

Methods:
We evaluated 299 coronary lesions by intracoronary pressure and flow velocity measurements to determine FFR and HMR. Myocardial perfusion scintigraphy (MPS) was performed to identify inducible myocardial ischemia. High HMR was defined as HMR>1.9 mmHg/cm/s. The association between FFR and inducible ischemia was evaluated according to the presence of a high or low HMR using logistic regression analysis. Receiver-operating characteristics curve analysis was performed to determine the optimal FFR cut-off value for inducible myocardial ischemia.

Results:
Overall, the odds ratio of positive versus negative FFR for inducible myocardial ischemia on MPS was 4.6 (95% confidence interval (CI): 2.6-8.0; p<0.001). The odds ratio of positive versus negative FFR for myocardial ischemia amounted to 2.1 (95% CI: 0.5-3.6; p=0.14) when HMR was low, and to 8.1 (95% CI: 4.0-16.5; p<0.001) when HMR was high. The optimal FFR cut-off value for inducible myocardial ischemia was 0.65 when HMR was low, compared with 0.76 when HMR was high.

Conclusion:
The 0.80 cut-off value provides limited discriminative value, since the odds for myocardial ischemia originating from FFR-positive lesions are to a large extent determined by the magnitude of distal microvascular resistance. The optimal FFR cut-off value to identify stenosis-related inducible myocardial ischemia depends on the magnitude of HMR, and is substantially lower when HMR is low, compared with when HMR is high.
Abstract 18248: Reduced β-catenin Expression in Mouse Cardiomyocytes Increases Matrix Metalloproteinase Activation and Apoptosis, Producing Greater Post-Infarction Ventricular Dysfunction
Authors: Singh Kaustabh , Mihic Anton , Hatta Kota , Amini-Nik Saeid , Wu Jun , Li Shu-Hong , Sun Lu , Alman Benjamin A , Brunt Keith R , Weisel Richard D , Li Ren-Ke
Published: April 2024

Introduction:
The loss of beating cardiomyocytes after myocardial infarction (MI) is followed by detrimental remodelling involving activation of matrix metalloproteinases (MMPs), which can lead to heart failure. β-catenin, a member of the cadherin family, is found at cell-cell junctions and can increase cell survival and promote tissue repair via canonical Wnt signaling. However, its role in the heart has not been characterized. We sought to determine whether β-catenin is important in cardiac remodelling after MI.

Hypothesis:
β-catenin signaling in cardiomyocytes mediates cell death and matrix remodelling and contributes to post-infarction ventricular dysfunction.

Methods/Results:
The role of β-catenin in cardiomyocytes was evaluated with transgenic mice harboring a floxed mutation for β-catenin driven by a muscle creatine kinase-Cre promoter. Mutant and wild-type (WT) mice were subjected to coronary artery ligation to induce MI, and cardiac function was evaluated by echocardiography. The β-catenin null mice exhibited a 16% decrease in ejection fraction compared to WT controls (69.2±0.9 vs. 59.6±1.0, p<0.05, n=7). Histology revealed greater cardiac thinning and dilatation in the null mice. Histological analysis demonstrated increased β-catenin protein expression in the nuclei of WT myocardium following ligation. TUNEL staining revealed 50% greater apoptosis in the border region of the infarcted myocardium of the null mice (p<0.05). Both WT and null mice had a 4-fold increase in the protein level of the apoptotic markers caspase3 and cleaved parp in the infarct scar compared to the remote region (p<0.05, n=4), which was similar between groups. Gel zymography (to assess MMP2 activity) demonstrated a 60% increase in MMP2 activation within the infarct region (p<0.05, n=4), and Western blot showed a 75% decrease in tissue inhibitor of metalloproteinase 3 (TIMP3) protein levels within the remote region of the null mice (p<0.05, n=4).

Conclusion:
The exaggerated ventricular dysfunction in the null mice following injury was due to the depletion of β-catenin in cardiomyocytes. Our data suggest that β-catenin is necessary for the modulation of MMP2 and cell apoptosis to prevent detrimental remodelling and heart failure following MI.
Abstract 18255: Inhibition of Toll-Like Receptor 4 Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation: Role of STAT3
Authors: Zhang Yali , Park Ho-Jin , Beasley Debbie , Galper Jonas
Published: April 2024

Abdominal aortic aneurysm (AAA) is a potentially life-threatening degenerative vascular disease that affects 6-9% of men over 65. Toll-like receptors (TLRs) mediate the innate immune response resulting in the recruitment of inflammatory cells to the site of a range of pathogen-associated molecular patterns; they have also been implicated in many other inflammatory diseases such as cancer and atherosclerosis. It has been suggested by others that TLR4 might play a role in AAA formation.

Objective:
The purpose of this study was to determine whether TLR4 and its related Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway contributed to the development of angiotensin II (AngII)-induced AAA formation.

Methods and Results:
AngII (750 ng/kg/min) was infused into either ApoE-/- or ApoE-/-TLR4-/- male mice at 4 month old for 28 days using osmotic minipumps. The expression of TLR4 protein was significantly increased in aneurismal tissues compared to control aorta. TLR4 deficiency profoundly reduced AAA, with incidence of AAA formation of 82% versus 39%, with external aortic diameters of 1.88±0.13 mm versus 1.28±0.20 mm (n=18) respectively. STAT3 activation as measured by levels of pSTAT3 was increased in AngII treated ApoE-/- mice compared to vehicle treated, and was markedly reduced in AngII treated ApoE-/-TLR4-/- mice. Furthermore, the TLR4 antagonist, Eritoran attenuated AAA formation, with incidence of AAA formation of 80% versus 50%, with external aortic diameters of 1.92±0.15 mm versus 1.35±0.18 mm (n=9) respectively. Eritoran treatment also decreased pSTAT3 in AngII-treated ApoE-/- mice. The JAK/STAT3 can be driven by both AngII and TLR4 signaling. In order to determine the role of STAT3 in AAA formation, S3I-201, an inhibitor of STAT3 was administrated. AngII-induced AAA formation in ApoE-/- was significantly prevented by S3I-201 treatment (5mg/kg, IP, QOD) with incidence of AAA formation of 85% versus 40%, with external aortic diameters of 1.90±0.16 mm versus 1.15±0.10 mm (n=15) respectively.

Conclusions:
These studies demonstrated that inhibition of TLR4 reduces AngII-induced AAA via a STAT3 dependent mechanism suggesting that selective targeting of STAT3 may have substantial therapeutic potential.
Abstract 18265: Determining the Adequacy of Pediatric CPR: CPP Associated With ROSC
Authors: Yuerek Mahsun , Ahmed Mubbasheer , Bhutta Adnan T , Prodhan Parthak , Sutton Robert , Schexnayder Steve M
Published: April 2024

Introduction:
Human adult studies have shown that the coronary perfusion pressure (CPP) correlates positively with return of spontaneous circulation (ROSC) during CPR. Paradis et al have shown that a CPP of at least 15 mmHg during CPR was associated with ROSC in adult patients.

We reviewed in-hospital CPR of pediatric patients between July 2010 and June 2012 at Arkansas Children’s hospital (ACH), who were admitted to the PICU or CVICU at the time of the cardiac arrest and had monitoring lines allowing determination of CPP.

Hypothesis:
We hypothesized that CPP increases during CPR and the necessary CPP for ROSC in pediatric patients is lower than reported for adults.

Methods:
Patients with cardiac arrests were identified through ACH CPR registry. CPP was calculated by subtracting the end-diastolic central venous pressure (CVP) from the end-diastolic arterial blood pressure (BP), representing the CPP prior to the next chest compression as defined by the Utstein criteria. We identified 43 patients that had invasive arterial BP and CVP monitoring at the time of the cardiac arrest. Complete monitoring data was available for 10 patients. The mean CPP was calculated in 15 seconds epochs.

Results:
The mean age for our 10 patients was 320 days (range 12 days - 5.53 years). 8 of the 10 patients had a diagnosis of congenital heart disease and 7 of these 8 patients were admitted to the CVICU for postoperative care. 6 patients were male and 4 were female. Mean weight was 5.8 kg. The mean duration of CPR was 194 seconds. All patients had ROSC; however one patient died within 24 hours of the cardiac arrest, two patients died more than 24 hours after the cardiac arrest. 7 of the 10 patients survived to hospital discharge. Mean CPP was significantly higher for the last 15 second epoch before ROSC compared to the initial 15 second epoch of CPR (22.96 mmHg (SD +/- 9.96 mmHg vs. 5.4 mmHg (SD: +/- 8.2 mmHg), P<0.001). The mean CPP for the minute of CPR prior to ROSC was 15.95 mmHg (standard deviation (SD): +/- 4.8 mmHg).

Conclusion:
CPP increased during CPR and was significantly higher just prior to ROSC. Mean values in the minute prior to ROSC were similar to that reported in adults. To our knowledge, this is the first descriptive study of CPP during CPR in pediatric patients.
Abstract 18285: Carnosine Supplementation Improves Metabolic Syndrome and Revascularization After Hindlimb Ischemia in Diet-Induced Obese Mice
Authors: Baba Shahid P , Zhang Deqing , Boakye Adjoa Boakye A , Fennigan Tess , Guo Luping , Bhatnagar Aruni , Conklin Daniel J
Published: April 2024

Critical limb ischemia (CLI) affects more than 10 million people in U.S. as a result of peripheral arterial disease. It is an important clinical condition that leads to claudication, increased risk of peripheral limb infection, gangrene and amputation. Although surgical revascularization can facilitate blood flow, obese and type 2 diabetic (T2D) CLI patients are poor candidates for revascularization surgery, and thus, we investigated a potential alternative therapy. Carnosine is an endogenous histidyl dipeptide present in high concentrations in skeletal muscle (1-20 mM). Previous studies of T2D patients showed that carnosine level is reduced in the gastrocnemius muscle. Similarly, 12 weeks high fat diet (HFD; 60% kcal fat) fed mice had significantly lower carnosine level in the gastrocnemius muscle (1.2±0.1nmol/mg tissue) than low fat fed (LFD; 2.8±0.5 nmol/mg tissue; n=6; P<0.05) as measured by LC-MS/ESI. To better understand the consequences of carnosine deficiency in obesity, we tested whether chronic supplementation of carnosine alters metabolic stress in HFD fed C57BL/6 mice. Carnosine supplementation (3g/l drinking water) for 6 weeks significantly attenuated body weight (43±1gm) and glucose tolerance in obese mice compared with untreated obese mice (49±2gm; n=12; P<0.05). Because carnosine quenches reactive oxygen and carbonyl species that can limit ischemic injury we also tested if carnosine supplementation could attenuate CLI in obese mice. Doppler perfusion imaging 14 days after femoral artery ligation in obese mice showed that carnosine (1gm/l) pretreatment (1 week and continued after ligation) significantly increased hindlimb (HL) blood flow recovery in treated mice to 56±3% of the non-ischemic control limb compared to untreated mice (34±3%;n=4;P<0.05).Similarly, in non-obese mice carnosine treatment also significantly increased HL blood flow recovery to (63±6%) of the non-ischemic control limb compared to untreated mice (19±3%;n=6; P<0.05).These findings show that carnosine mitigates effects of diet-induced metabolic syndrome, and improves angiogenesis and thus may be a potential inexpensive and safe therapeutic for attenuating metabolic syndrome and increasing revascularization in obese patients suffering CLI.
Abstract 18291: Vascular Smooth Muscle Cell Stiffness as a Novel Mechanism for the Increased Aortic Stiffness in Aging and Hypertension, Which is Augmented in Aging Hypertensive Animals
Authors: Sehgel Nancy L , Zhu Yi , Sun Zhe , Hunter William C , Trzeciakowski Jerome P , Vatner Dorothy E , Meininger Gerald A , Vatner Stephen F
Published: April 2024

It is generally recognized that increased aortic stiffness occurs in hypertension and aging. However, less is known about their combined influence on aortic stiffness. Furthermore, most prior studies have attributed increased aortic stiffness to changes in the extracellular matrix, whereas the hypothesis of this investigation is that a significant component of vascular stiffness resides at the level of the vascular smooth muscle cells (VSMCs), and that the contribution of this mechanism would be enhanced when aging is superimposed on hypertension. Testing of this hypothesis was made possible by examining VSMC the mechanical properties of isolated VSMCs using atomic force microscopy (AFM). We examined aortic stiffness in young (16 wks) and old (64 wks) spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) wild-type controls and tested the hypothesis that the additional increase in aortic stiffness with combined aging and hypertension is mediated, in part, at the level of VSMCs. Systolic aortic pressure, measured by Millar micromanometer catheter, was significantly increased in the old compared to young SHR (191 ± 8 mmHg versus 148 ± 5 mmHg, p<0.01), but not in WKY (old, 101 ± 10 mmHg versus young, 120 ± 8 mmHg). Excised aortic ring segments were subjected to physiological levels of mechanical stretch ex vivo, and the wall stress in these ring segments was greater in older SHR than WKY (p<0.05). VSMCs were isolated from the thoracic aorta, and the stiffness of individual VSMCs was measured by an AFM nano-indentation technique. Isolated VSMC stiffness was 43 ± 8% greater, p<0.05, in old SHR compared to young SHR (27 ± 4 kPa). VSMC stiffness was also increased, p<0.05, in young SHR versus young WKY (14 ± 2 kPa), but this increase (92 ± 15%) was less, p<0.05, than that observed between old SHR versus old WKY (131 ± 2%). Thus, increased VSMC stiffness is a significant component of the increased aortic stiffness of hypertension, but this increase is augmented in aging hypertensive rats.
Abstract 18310: Therapeutic Use of Encapsulated Genetically Engineered Mesenchymal Stem Cells for Vascular Regeneration
Authors: Takemiya Kiyoko , Titterington Jane S , Joseph Giji , Weiss Daiana , Lyle Alicia N , Caesar Christa , Safely Susan A , Weber Collin J , Galipeau Jacques , Taylor W. Robert
Published: April 2024

Background:
We have previously shown that encapsulation of mesenchymal stem cells (MSCs) in alginate improves cell retention and efficacy of stem cell therapies in the hind limb model of vascular insufficiency. Erythropoietin (EPO), a hematopoietic cytokine, is also known as an angiogenic factor. The purpose of this study is to evaluate the efficacy of encapsulated, gene transfected MSCs as therapeutic strategy for enhancing collateral formation in hind limb ischemia model by using EPO transfected MSCs (MSC-EPO).

Methods and Results:
MSCs and MSCs-EPO were encapsulated into alginate microcapsules. Hind limb ischemia was induced by ligating and excising both the super facial femoral artery and vein in the left leg. The mice were implanted with either empty capsules, encapsulated 1 X 10
6
MSCs (MSC group), encapsulated 0.9 X 10
6
MSCs + 0.1 X 10
6
MSCs-EPO (low EPO group), or encapsulated 0.5 X 10
6
of MSC + 0.5 X 10
6
of MSCs-EPO (high EPO group). Blood analysis was performed on post-operative day (POD) 14 and 28 and histological evaluation with immunohistochemistry was performed on POD 14 (n=4/group). To evaluate the functional recovery, a spontaneous running wheel test was performed between POD 14 to POD 21. On POD 14, there was no significant change in hematocrit in 4 groups. On POD 28, the hematocrit in the high EPO group was significantly increased (57.2±4.6%) Histological evaluation revealed that the density of collateral vessels was increased in both the low and high EPO groups. (0.7±0.04, 0.84±005, 0.98±0.05 and 1.06±0.06 respectively) Although the high EPO group had a much higher density of collateral vessels, the running distance was significantly reduced to two third of the other groups.(6507±208.3, 6223±294.0, 6067±510.5 and 3952±322.1m/day, respectively)

Conclusion:
The use of alginate encapsulation of MSCs is a viable strategy for site directed gene therapy. Our data show that EPO can be effectively delivered resulting in an improvement in collateral vessel formation. However, chronic over-expression of EPO may cause adverse effects likley as a result of increased blood viscosity.
Abstract 18317: An Interactive Online Education Program Improves Knowledge of ECG Monitoring: Findings From the PULSE Trial
Authors: Funk Marjorie , May Jeanine L , Stephens Kimberly , Fennie Kristopher P , Chang Pei-Shiun , Winkler Catherine , Feder Shelli L , Drew Barbara J ,   PULSE Site Investigators
Published: April 2024

Introduction:
Evidence suggests that ECG monitoring practices are inconsistent and inadequate, which may be due to knowledge deficits of nurses. We evaluated whether an interactive online education program improves knowledge related to ECG monitoring.

Methods:
The PULSE Trial is a 5-year multi-site randomized clinical trial with crossover to evaluate the effect of implementing the AHA practice standards for ECG monitoring on nurses’ knowledge, quality of care, and patient outcomes. We report data related to nurses’ knowledge from all 3 phases. The sample included nurses on cardiac units in 14 hospitals. After nurses completed a validated 20-item knowledge test, hospitals were randomized to the experimental or control group. Experimental group nurses completed the education program that covered essentials of ECG monitoring and arrhythmia, ischemia, and QT interval monitoring. They then re-took the knowledge test. In phase 3, 12-18 months later, experimental group nurses re-took the test to evaluate knowledge retention and control group nurses took the education program and test. We used mixed modeling to address repeated measures and hospital intra-correlation.

Results:
The sample contained 2,560 unique nurses (90% female, 75% white, mean age 38±11 years).

Mean test scores improved (p<.0001) in both groups (71.2) immediately after the intervention, but declined to 61.1 12-18 months later in the experimental group. This was lower (p<.0001) than right after the intervention, but higher (p<.0001) than before. Of the 4 subsections of the test, essentials of ECG monitoring had the highest mean post-test scores (77) and ischemia monitoring had the lowest (56). The pattern of change for all subsections was similar to the entire test.

Conclusions:
Although test scores improved after the education, gains diminished over time, but were better than at baseline. Whether the improved knowledge translates into better quality of care and patient outcomes will be determined.
Abstract 18319: Cardiac Services for Care of Suspected Acute Coronary Syndromes in Australia and New Zealand Hospitals
Authors: Ranasinghe Isuru , Astley Carolyn , Aliprandi-Costa Bernadette , Chew Derek , Ellis Christopher J , Hammett Christopher J , Briffa Tom G , Howell Tegwen E , Lintern Karen J , Parker Hella , Carr Bridie , Gamble Greg D , Tavella Rosanna , Redfern Julie , French John , Brieger David
Published: April 2024

Background:
Population-wide assessment of cardiac services recommended for optimal acute coronary syndromes (ACS) care has not been previously performed. We assessed the availability of ACS services among hospitals in Australia and New Zealand.

Method:
Services recommended for optimal ACS outcomes were identified from ACS guidelines and clinical consensus, and were collected from hospitals using a structured questionnaire. Thirty services reflecting acute care, investigations and procedures, management of complications, and preventative services were included. Data on consecutive ACS admissions over 2 weeks was simultaneously collected.

Results:
Of the 433 acute hospitals in both countries, 273(63%) provided service characteristics and 243(89%) provided patient data (n=2287 ACS patients). Figure shows the availability of selected services. Among hospitals, an emergency physician was available in 50%, cardiology consultation was available acutely in 35% and 22% provided primary PCI. Most investigations/procedures were available in <50% of hospitals except exercise stress testing (58%) and echocardiography (56%). A CCU was present in 52%, 44% provided an inpatient cardiology service, 52% provided a follow-up clinic and <40% provided an outpatient heart failure program or a readmissions reduction program. Service availability varied markedly among hospitals (median 14 services,IQR 7-30). Among hospitals that collected patient data, 25% of all patients presented to hospitals with <50%(15/30) of services and only 40% were cared at hospitals with >80%(24/30) services available. Service availability was not correlated with in-hospital outcomes although the study lacked sufficient power.

Conclusion:
The availability of cardiac services for optimal ACS care varies widely in Australian and New Zealand hospitals. Such inequalities resulting from uncoordinated dissemination of healthcare resources may contribute to variations in ACS outcomes
Abstract 18345: Coronary Artery Disease With Acute Myocardial Infarction, but Not Without, is an Independent Risk Factors for Incident Heart Failure Among Community-Dwelling Older Adults
Authors: Hashim Taimoor , Elbaz Shereen , Fonarow Gregg C , Prabhu Sumanth D , Patel Kanan , Morgan Charity J , Aronow Wilbert S , Ahmed Ali
Published: April 2024

Background:
Coronary artery disease (CAD) is a major risk factor for heart failure (HF) in older adults. Whether this risk varies by the presence of prior acute myocardial infarction (AMI) remains unclear. We examined the independent of association of non-AMI CAD and AMI with incident HF.

Methods:
Of the 5521 participants in the Cardiovascular Health Study (CHS) without baseline HF, 4558 were free of baseline CAD. Using these no-CAD participants as reference, we assembled two pre-match cohorts including (1) 519 with non-AMI CAD (n=5077) and (2) 444 with AMI (n=5002). We then assembled two propensity-matched cohorts of 379 pairs (non-AMI CAD vs. no-CAD) and 325 pairs (AMI vs. no-CAD) of participants, both balanced on 65 baseline characteristics (mean age, 74 (±6) years in both).

Results:
During 13 years of follow-up, incident HF occurred in 24% and 28% of matched participants with no CAD and non-AMI CAD, respectively (hazard ratio {HR}, 1.21; 95% CI, 0.91-1.60; P=0.190), and in 27% and 38% of matched no-CAD and AMI participants, respectively (HR, 1.70; 95% CI, 1.29-2.24; P<0.001;
Figure
).

Conclusions:
Among community-dwelling older adults, compared to no CAD, those with AMI but those with non-AMI CAD, had independent association with incident HF. These findings suggest that the presence of AMI may be used to risk stratify older adults at higher risk for HF for preventative efforts.

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Abstract 18350: A Composite Risk Score of Biomarkers of Inflammation, Thrombosis, and Cell Stress Pathways Significantly Predict Risk of Adverse Cardiovascular Outcomes
Authors: Ghasemzadeh Nima , Al Kassem Hatem , Eapen Danny , Khayata Mohamed , Tahhan Ayman S , Manocha Pankaj , Alzaraneh Bushra , Nanjundappa Ravi , Thorball Chrsitian W , Patel Riyaz , Lerakis Stamatios , Sperling Laurence , Pielak Tomasz , Sikora Sergey , Epstein Stephen E , Quyyumi Arshed A
Published: April 2024

Background:
An aggregate biomarker risk score of C-reactive protein (CRP), heat shock protein (HSP)-70, and fibrin degradation products (FDP) significantly predicts adverse outcomes in patients with CAD. Soluble Urokinase Plasminogen Activator Receptor (suPAR) is an inflammatory biomarker that has been associated with incident CVD. We sought to investigate the value of adding plasma suPAR level to the 3 original biomarkers in predicting risk of adverse outcomes.

Methods:
3,280 patients (aged: 62± 11, 83% white, 32% diabetics, 64% with CAD ≥50%) undergoing diagnostic angiography were followed for death and/or MI over median 2.3 yrs. Plasma suPAR (ViroGates, Denmark), and serum CRP, HSP-70, and FDP (Firstmark Inc) were measured using ELISA. Severity of CAD was assessed by the Gensini score. Cox proportional survival and C-statistic analyses were performed adjusting for traditional risk factors, ejection fraction, serum creatinine, and Gensini.

Results:
Patients with suPAR level ≥ 3.5ng/ml (ROC cutoff) had a greater CAD burden (Gensini: 49± 68 vs. 41± 64, p=0.003). Plasma suPAR ≥ 3.5 also predicted future death/MI (HR=1.76, p<0.001) after adjustment for all covariates and the 3 biomarkers, CRP, HSP-70, and FDP; the C-statistic improved (0.69 to 0.71, p=0.01). A 4 biomarker aggregate score composed of suPAR, CRP, FDP, and HSP-70 below/above cutoffs significantly predicted risk of death/MI. Thus, compared to those with 0 biomarkers, HR of death/MI for those with 1, 2, 3, or 4 positive biomarkers were: 1.5, 2.1, 4.4, and 7.3 respectively (P<0.001). Addition of the 4-marker score significantly improved the C-statistic compared to a model of traditional factors (0.68 to 0.75, p=0.004).

Conclusion:
An aggregate risk score of CRP, HSP-70, FDP, and suPAR representing inflammatory, thrombotic, and cell stress pathways, identifies CAD patients at low and very high risk of death/MI. Thus, the score allows individualization of risk in CAD patients.
Abstract 18356: Autologous Intracoronary Stem Cell Therapy is Safe and Feasible for Children With Dilated Cardiomyopathy: A Randomised Controlled Cross-Over Pilot Study
Authors: Pincott E. Sian , Ridout Deborah , Brocklesby Margaret , McEwan Angus , Muthurangu Vivek , Burch Michael
Published: April 2024

Meta-analysis of adult stem cell therapy studies post myocardial infarction has shown moderate & sustained improvement of function. Positive results have also been seen in adult dilated cardiomyopathy (DCM) & chronic ischaemic heart failure. The place of stem cells in pediatric heart failure is unknown.

This randomised, blind, crossover placebo controlled trial sought to evaluate the potential use of stem cells in the management of pediatric heart failure & is the first of its kind within the pediatric population.

Methods & results:
Ten children (mean age 7.2y, range 2.2-14.1y, 6 male) with DCM were recruited from Heart Failure clinic. Patient profiles on study entry: NYHA/Ross class 3-4, ejection fraction (EF) on MRI mean 40% (range 30-48%). On enrolment patients were randomised to receive stem cell or placebo intracoronary injection & MRI, with cross-over of intervention at 6 months & final MRI assessment at 1 year. Bone marrow processing was performed using standard techniques. The mononuclear cells, obtained within 1.5 hours of aspiration, were divided to provide 1ml for coronary injection & 1ml for phenotyping. Intracoronary injections & MRI were performed under the same anaesthetic. Mononuclear cell count mean was 51.7 x 106/ml (range 11.8-115.1 x 106/ml).

Nine patients completed the protocol, the tenth patient had Duchenne Muscular Dystrophy (DMD) & did not undergo general anaesthesia, this data was excluded from the group analysis and is presented separately. There were no withdrawals, morbidity or mortality.

Primary end point, freedom from death or transplant, was achieved in all patients. Secondary end points, indexed end diastolic volume (EDV) 6 months post cell infusion for n=9, was reduced in 7 & unchanged in 2 (P=0.01 for comparison of means), end systolic volume (ESV) decreased in 6 following cell injection. (P=0.05 for comparison of means). EDV increased in 5 patients following placebo. EF did not change significantly. EDV reduced in all patients with an injected cell count >34.2 x 106.

Conclusion:
This pilot study demonstrates that intracoronary injection of autologous stem cells is safe & feasible in children. Encouraging data on EDV were generated, larger scale studies will be required to measure clinical effect.
Abstract 18366: Disruption of Histone Deacetylase 4 Sumoylation Promotes Hypoxia-Induced Injury in Cardiomyocytes
Authors: Du Jian Feng , Zhao Ting C
Published: April 2024

Background:
Histone deacetylase (HDAC) inhibition has been shown to play an important role in eliciting cardioprotection. However, molecular mechanism(s) of HDAC modification that mediate the survival of myocytes remains unknown. Objectives: The goal of this study is to test whether disruption of HDAC4 sumoylation abolishes HDAC inhibitor-induced protective effects in H9c2 cardiomyocytes exposed to hypoxia/reoxygenation, and whether HDAC inhibitor leads HDAC4 sumoylation, which cause subsequent HDAC4 ubiquitination.

Methods:
Rat H9c2 cardiomyocytes were cultured and then subjected to hypoxia for 48 hours followed by 2 hours of re-oxygenation. Cardiomyocytes were preconditioned with trichostatin A, a selective HDAC inhibitor that blocks HDAC activity. To further examine the function of HDAC4 sumyolation in the regulation of HDAC inhibition-induced protective effects, stable cardiomyocyte lines expressing wild type HDAC4 and dead HDAC4 sumoylation (HDAC4K559R) were established, respectively. Cell cytotoxicities were estimated by the measurement of lactate dehydrogenase (LDH) leakages. The cell viabilities were assessed by MTT assay. Western blot and immunoprecipitation were employed to detect HDAC4 protein sumoylation following HDAC inhibition.

Results:
Inhibition of HDAC increased the resistance of cardiomyocytes against hypoxia-reoxygenation, as indicated by the reduction in LDH leakage and the increase in cell viabilities. As compared with wild type HDAC4 over-expressing of cardiomyocytes, disruption of HDAC4 sumoylation at lysine 559 increases the susceptibility of cardiomyocytes to hypoxia-reoxygenation injury. Western blot and co-immunoprecipitation assay demonstrated that HDAC inhibition-mediated HDAC4 sumoylation was associated with ubiquitination of HDAC4.

Conclusion:
Our study demonstrated that HDAC inhibition produces protective effects in cardiomyocytes, which is modulated by specific HDAC4 sumoylation.