bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 16666: Comparison of Wall Stresses After Ross Procedure Using Ex-Vivo Pulmonary Autograft vs in-vivo Autograft Imaging
Authors: Xuan Yue , Wang Zhongjie , Kumar Shalni , El-Hamamsy Ismail , Pierre-Mongeon Francois , Leask Richard , Ge Liang , Tseng Elaine
Published: April 2024

Introduction:
Ross operation provides young adult and pediatric patients a living valve with excellent hemodynamics and no lifelong anticoagulation. However, autograft dilatation is a concern when it leads to aneurysm formation and autograft insufficiency requiring reoperation. Computational simulations of autograft remodeling are potentially effective to predict autograft dilatation, but require zero-pressure geometry and patient-specific material properties for accuracy.

Hypothesis:
We hypothesized that pulmonary autograft wall stresses estimated from computational simulations using in-vivo imaging would reasonably correlate with the gold standard, wall stresses determined computationally using ex-vivo autograft specimens at zeto-pressure. We recently showed that autograft wall stresses significantly increased immediately after the Ross operation. Our goal was to compare autograft wall stresses based on in-vivo geometry to those based on ex-vivo autografts.

Methods:
Magnetic resonance imaging (MRI) was obtained in pre-operative Ross patients and used to reconstruct in-vivo autograft geometry. Pre-stress (zero-pressure) geometry was determined. As controls, pulmonary autografts explanted from normal donor hearts underwent micro-computed tomography scans for reconstruction of ex-vivo geometry. Biaxial stretch testing was performed on both intraoperative tissue from Ross patients and on ex-vivo autografts to determine patient-specific material properties. Finite element simulations using LS-DYNA were performed to determine wall stresses.

Results:
Imaging from ex-vivo pulmonary autografts (n=6) and Ross patients (n=6) were obtained. Peak stresses were 93 kPa for ex-vivo vs. 113 kPa for in-vivo autografts at 25mmHg and 448kPa vs. 558 kPa, respectively at 120mmHg.

Conclusions:
Wall stresses at pulmonary and systemic systolic pressure predicted by in-vivo MRI imaging reasonably correlated with wall stresses based upon ex-vivo autograft tissue. Computational simulations using in-vivo imaging provides a suitable surrogate for the gold standard simulations using ex-vivo tissue specimens and broadens clinical applicability of computational simulations for patient-specific outcomes.
Abstract 16670: Urocortin 2 Gene Transfer Reduces the Adverse Effects of Western Diet on Cardiac Function in Mice
Authors: Kim Young Chul , Giamouridis Dimosthenis , Lai Ngai C , Guo Tracy , Xia Bing , Fu Zhenxing , Gao Mei Hua , Hammond H. K
Published: April 2024

Diabetes mellitus increases the risk of heart failure. We previously showed that injection of adeno-associated virus 8 encoding urocortin 2 (AAV8.UCn2) increases glucose disposal in insulin resistance and improves function of the failing heart in mice. In the present study, we tested the hypothesis that UCn2 gene transfer would have beneficial effects in diabetic cardiomyopathy. Eight-week-old C57Bl/6J male mice were fed normal chow (NC) or a Western diet (WD, 35% kcal carbohydrate and 45% fat) for 30w, and then received saline or AAV8.UCn2 (1.9x10
13
genome copy/kg) via intravenous injection. Before and 10w after gene transfer, we measured fasting blood glucose, glucose tolerance, and cardiac function via echocardiography and rates of LV pressure development (+dP/dt) and decline (-dP/dt) using micromanometers. We also measured key signaling proteins in the left ventricle (LV). Western diet increased 12h fasting glucose levels compared to normal chow (81% increase; p<.0002). WD vs normal chow reduced LV peak +dP/dt (p=.042) and LV peak -dP/dt (p=.027), although LV ejection fraction (EF) was unchanged. Thus WD induced diabetes and cardiomyopathy with normal EF. Among mice fed WD, UCn2 gene transfer reduced fasting glucose (WD+Saline: 190±11 mg/dL, n=8; WD+UCn2: 149±6 mg/dL, n=8; p=.006), increased LV peak +dP/dt (p=.005;
Fig A
), LV peak -dP/dt (p=.007;
Fig B
), and reduced Tau (p=.016;
Fig C
). In addition, among WD-fed mice, UCn2 gene transfer increased LV EF (p=.005) and the velocity of circumferential fiber shortening (p=.0005). LV samples from WD+UCn2 mice showed increased phosphorylation of PKA catalytic domain (WD+Saline: .2±.04, n=5; WD+UCn2: .3±.02, n=5; p=.03). In conclusion, UCn2 gene transfer increased LV systolic and diastolic function and reduced blood glucose in mice with diabetic cardiomyopathy.
Abstract 16675: Association Between Cardiovascular Risk Factors and Sedentary Behavior Prevalence: A Cross-Sectional Analysis of the National Health Survey-2013
Authors: Helal Lucas , Domingues Marlos R , Umpierre Daniel
Published: April 2024

Introduction:
Sedentary behavior (SB) independently increases the risk of CV disease, as well as of CV and all-cause mortality. However, it is still unknown how the prevalence of the detrimental amounts of SB is affected by CV risk factors prevalences. To do so, we aimed to estimate the association between the prevalences of traditional CV risk factors and television watching time ≥ 4 hours/day (TV4) in adults (≥ 18 years old).

Hypothesis:
We hypothesized that CV risk factors prevalences would be independently associated with the prevalence of TV4.

Methods:
This is an analysis of the 2013’s Brazilian National Health Survey. We sought to estimate how the prevalence of age ≥ 35 years old, obesity (BMI ≥ 30 kg/m
2
), sleep disturbance episodes (SD) in the last two weeks, major depression (MD), hypertension (HYP) and diabetes mellitus (DM) diagnosis could be independently associated with TV4. A Poisson’s regression was carried out in 36,714 adults within a three-step level of predictors and TV4 to achieve the final model, as follows: age (1); BMI, SD and MD (2); HYP and DM (3). All the risk factors remained at the final. Also, a model with and without SD was also conducted to address its potential confounding role with the other risk factors. Prevalence ratios (PR) with 95% confidence intervals (95%CI - α=0.05). Whenever necessary, variables were dichotomized from their original categories. Age was originally collected as a continuous variable.

Results:
We found a TV4 prevalence of 15.65% (95%CI 15.37-15.95%). In our final model, all CV risk factors prevalences remained independently associated with TV4 prevalence. More specifically, age ≥ 35 years old was associated with a decrease in TV4 prevalence (PR 0.82, 95%CI 0.78-0.87), whereas obesity (PR 1.25, 95%CI 1.17-1.32), SD (PR 1.36, 95%CI 1.28-1.45), MD (PR 1.09, 95%CI 1.01-1.19), HYP (PR 1.16, 95%CI 1.09-1.24 and DM (PR 1.17, 95%CI 1.12-1.22) were associated with increasing. Moreover, when removing SD from the final model, the association between MD and TV4 was the only modified and increased (1.19, 95%CI 1.09-1.29).

Conclusions:
The prevalences of CV risk factors were independently associated with the detrimental amounts of SB. SD attenuated the RP between MD and TV4, leading us to speculate a potential role of SD in the attributable TV4 prevalence for MD. Our findings disclaim a potential risk factor loop scenario and reinforce the need to test whether the reduction of SB could reduce CV risk factors or not, including a special attention on SD, to better clarify any potential causal relationship among our studied risk factors.
Abstract 16678: A Novel p38-Alpha MAPK Inhibitor Reverses Sugen/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats
Authors: Alencar Allan Kardec N , Silva Grazielle F , Silva Marina M , da Silva Jaqueline S , Araujo Josenildo S , Montagnoli Tadeu L , Freitas Rosana C , Fraga Carlos A , Sudo Roberto T , Zapata-Sudo Gisele
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling with subsequent right ventricular (RV) failure.

Hypothesis:
The p38-alpha mitogen-activated protein kinase (p38-α MAPK) plays a pathogenic role in PAH. This work investigated the effects of a selective p38-alpha MAPK inhibitor, named LASSBio-1824, on hypoxia + SU5416 -induced PAH.

Methods:
Male Wistar rats (180-220 g) were exposed to 3 weeks of hypoxia and i.p. injection of VEGFR antagonist (SU5416; 20 mg/kg/week). Experimental groups were: Control + vehicle (DMSO), SuHx + vehicle (PAH group) and SuHx + LASSBio-1824 (20 mg/kg/day for 2 weeks).

Results:
Pulmonary acceleration time (ms) was reduced from 44.7 ± 1.1 (control) to 20.6 ± 1.7 in SuHx + vehicle group (P < 0.05) and restored to 38.9 ± 2.9 in SuHx + LASSBio-1824 group (P< 0.05). RV systolic pressures (mmHg) were increased from 30.1 ± 3.2 (control) to 109.5 ± 7.5 in SuHx group and reduced to 47.5 ± 5.3 after treatment with LASSBio-1824 (P < 0.05). The medial wall thickness of distal pulmonary arterioles (< 50 μm) was measured by immunohistochemistry for alpha-SMA expression which was increased from 40.7 ± 3.5 % (control) to 64.1 ± 3.1 % in PAH animals (P < 0.05) and was reduced in the treated group (52.2 ± 2.9). Acetylcholine-induced maximal relaxation (% ) in pulmonary arteries was reduced from 77.9 ± 5.2 to 17.2 ± 3.5 in PAH group. LASSBio-1824 increased that response to 67.8 ± 5.6 % (P < 0.05), indicating the ame- lioration of endothelial function. RV hypertrophy was detected because its wall thickness (mm) increased from 0.56 ± 0.02 (control) to 1.3 ± 0.03 in SuHx + vehicle group (P < 0.05) and the ratio between RV and left ventricle + septum increased from 1.50 ± 0.03 to 2.0 ± 0.2. Treatment with LASSBio-1824 significantly reduced the RV hypertrophy (ratio of 1.7 ± 0.07).

Conclusion:
The inhibition of p38-alpha MAPK isoform by LASSBio-1824 represents an impor- tant approach for the treatment of PAH in the future, which improves the underlying remodeling and inflammation processes.
Abstract 16689: Simultaneous Assessment of Cardiac Metabolism and Function Using PET/MR With Continuous FDG Infusion
Authors: Razalan Mary Grace Francheska , Centanni Ryan , Barton Gregory P , McMillan Alan B , Goss Kara N
Published: April 2024

Background:
We recently demonstrated the feasibility of simultaneous assessment of cardiac contractile function and metabolism in an animal model via positron emission tomography/magnetic resonance imaging (PET/MRI) with continuous
18
F-fluorodeoxyglucose (
18
F-FDG) infusion. The aim of this study is to determine feasibility of utilizing continuous FDG infusion in human subjects to assess real-time response to cardiac stressors.

Methods:
Subjects underwent standard cardiac MRI while receiving continuous FDG infusion for 60 minutes, with the first 15 minutes in normoxia (FiO2 = 0.209) followed by 45 minutes in hypoxia (FiO2=0.12). Contractile response was measured via MRI analysis. For PET analysis, 3D regions of interest (ROIs) were drawn over the left ventricle, paraspinal muscles, right hepatic lobe, and blood pool. Average ROI values were extracted to develop time-activity curves, which were used to quantify the uptake (Ki) in each tissue of interest using Patlak Analysis (Figure 1). A paired t-test was used to compare changes from normoxia to hypoxia.

Results:
Hypoxia resulted in expected nonsignificant hemodynamic changes (Table 1). While skeletal muscle and liver showed significant decreases in glucose uptake during hypoxia, the myocardium did not demonstrate a significant shift in activity in this small sample size.

Conclusion:
Simultaneous PET/MR with continuous FDG infusion captures real time cardiac contractile activity and metabolism. Further investigation to refine this novel, noninvasive modality will be useful to study early shifts in cardiac metabolism and reserve, which may precede development of overt heart failure.
Abstract 16706: The Use of a Precision Medicine Blood Test in a Rural Setting May Reduce the Need for Unnecessary Patient Travel to Undergo Advanced Cardiac Testing
Authors: Chronos Nicolas , Wilson Leigh Ann , Mc Allister Todd , Poteh Pafe , Coke Sallie , Huang Lin , Johnson Andrea , Kuo Jane Z , Monane Mark , Azarmina Pejman
Published: April 2024

Introduction:
Patients in the rural setting have been shown to have less access to specialist care. More effective tactics are needed to evaluate symptomatic patients with suspected obstructive coronary artery disease (CAD) in this setting. A blood-based age/sex/gene expression score (ASGES) incorporating key features of precision medicine has shown clinical validity with a 96% negative predictive value and 89% sensitivity in estimating a symptomatic patient’s current likelihood of obstructive CAD.

Objective:
The objective of this retrospective study was to evaluate the use of an ASGES and its effects on unnecessary testing and patient travel burden for rural patients with suspected ischemic heart disease.

Methods:
Medical records of 112 symptomatic patients with no previous advanced cardiac testing were analyzed at a single, rural-based cardiology clinic from 2014 to 2016. Demographics, clinical characteristics, and ASGES (predefined as low
<
15 and elevated > 15) results, as well as follow-up for major adverse cardiac events (MACE) and coronary artery revascularizations were collected for analysis (median follow-up of 389 days). Mileage is calculated as the cumulative distance from a patient’s zip code to the care center using Google map. Patients who had concomitant diagnoses outside of intended use were excluded.

Results:
Among 112 patients, 58 (52%) had a low score of ≤15, with an average ASGES of 7 (interquartile range 3.5 -11). Of the 58 patients with low scores, the average age was 59 (±13), 54 (93%) were women, 47 (81%) were white, and 49 (84%) had typical angina symptoms. With respect to a decrease in travel burden, the majority of low score patients (59%) made more than one trip following the initial workup, traveling a median of 325 miles. Among the 112 patients, MACE/revascularization was found in 2 patients (2 events) with low ASGES compared to 4 patients (9 events) in the elevated ASGES group.

Conclusions:
This study highlights the potential utility of a simple blood test in the rural setting to rule out obstructive CAD and avoid unnecessary travel burden for advanced cardiac testing. Almost half of the eligible patients had a low score and were at low current likelihood for obstructive CAD, thus they were unlikely to benefit from further testing.
Abstract 16709: Multicenter Assessment of Wearable Cardioverter Defibrillator Use in Patients at Risk of Sudden Cardiac Death: France National Experience
Authors: Marijon Eloi , Combes Nicolas , Gras Daniel , Sadoul Nicolas , Guedon-Moreau Laurence , Leclercq Christophe , Extramiana Fabrice , Lellouche Nicolas , Defaye Pascal
Published: April 2024

Hypothesis:
The wearable cardioverter defibrillator (WCD) has been shown to be useful during transient periods of high sudden cardiac death risk. This Registry was designed to provide real-world data on WCD use in France, in terms of compliance, potential adverse events, as well as efficacy.

Methods:
Multicenter evaluation (WEARIT FRANCE Registry) was conducted in France between January 2017 and March 2018. Overall, 1013 patients with complete data sets were analyzed: 834 with ischemic heart disease (82%, including 577 patients after myocardial infarction), 111 after ICD explant (11%), and 68 pre-transplant (7%). The median age was 61 years; the median ejection fraction was 25.4%.

Results:
Median WCD wear time was 61 days, with median daily use of 23.4 hours. Less than 1% of patients did not wear WCD at least 4 hours per day. During follow-up, a total of 35 sustained ventricular tachyarrhythmias (VT/VF) occurred in 30 patients, of whom 56.7% (n=17) received appropriate WCD shocks, giving an incidence of appropriate therapy of 1.7%
.
The rate of all VT/VF episodes were 2.9% among patients with ischemic cardiomyopathy (n=24/834) versus 3.3% for the others (n=6/179). Of the ischemic patients wearing beyond 30 days (N=657), 7 received appropriate therapy. Overall shock survival was 100%. Supra-ventricular tachycardia occurred in 6 patients. At the end of the WCD period, 564 patients (55.7%) were implanted with an implantable cardioverter defibrillator. Among the patients who had an ejection fraction below 35% at baseline, and were not implanted with an implantable cardioverter defibrillator (N=416), 351 (82%) had an improvement in ejection fraction to >35%. Five patients (0.49%) received inappropriate WCD shocks.

Conclusions:
In this multicenter nationwide WCD evaluation, 3% of patients presented with sustained VT/VF with 40% of those patients developing VT/VF after 30 days. The incidence of inappropriate therapy was low. These data suggest that the WCD, when worn appropriately, may be helpful in the arsenal to protect high-risk patients against SCD, especially in case of transient risk situations.
Abstract 16722: L-2-Hydroxyglutarate Protects Against Myocardial Ischemia-Reperfusion Injury
Authors: HE Huamei , Mulhern Ryan M , Xiao Wusheng , Oldham William , Lin Yi-Dong , Liao Ronglih , Loscalzo Joseph
Published: April 2024

Background:
L-2-hydroxyglutarate (L2HG) couples mitochondrial (Mito) and cytoplasmic energy metabolism in a model of cellular redox regulation. Under conditions of limited oxygen availability, mammalian cells generate L2HG to counteract the adverse effects of Mito reductive stress induced by hypoxia. L2HG is oxidized to α-ketoglutarate by L2HG dehydrogenase (L2HGDH) in a variety of mammalian tissues, including the heart. Myocardial ischemia/reperfusion injury (MIRI) is a consequence of coronary vascular disease and vascular procedures. Mito oxidative stress plays a critical role in MIRI. Here we hypothesized that L2HG protects against MIRI.

Methods and Results:
We induced accumulation of L2HG by heterozygous (HET) and homozygous (KO) deletion of L2HGDH gene in mice. The hearts isolated from HET, KO, and wild-type (WT) littermate mice were subjected to 30 min global thermal ischemia followed by 60 min reperfusion. Cardiac function and energy metabolism were simultaneously measured using a Langendorff heart perfusion model and
31
P-NMR spectroscopy. We found that female HET and KO exhibited better recovery of cardiac function post-MIRI in consistent with better preservation of intracellular ATP and phosphocreatine (Table). Using HPLC, we measured compounds representative of cellular redox state (GSG, GSSG, NAD, NADH, NADP, NADPH, coenzyme A and ascorbate), cellular energy state (ATP, ADP, AMP, GTP, GDP, GMP, UTP, UDP, UMP, CTP, CDP, CMP, IMP, malonyl-CoA and acetyl-CoA), and nucleotide catabolism (adenosine, hypoxanthine, xanthine and inosine) in freeze-clamped hearts. We found that ratios of GSH/GSSG and ATP/ADP increased in HET and KO hearts (Table). Interestingly, the ratios of NADH/NAD and NADPH/NADP increased only in KO but not in HET hearts. Consistent with the increased ratio of ATP/AMP, hypoxanthine and xanthine decreased only in KO hearts but not in HET hearts (Table).

Conclusion:
The accumulation of L2HG in a genetic mouse model protects against MIRI though increasing cellular antioxidative capacity and preserving high energy phosphates. The underlying mechanism of these beneficial adaptive phenomena warrants further study. Targeting L2HG levels and L2HGDH expression may serve as new therapeutic strategies for MIRI protection.
Abstract 16737: Cardiopulmonary Fitness and Cardiac Reserve 12-Months Following the Completion of Anthracycline-Based Chemotherapy With or Without Concurrent Exercise Training
Authors: Howden Erin J , Foulkes Steve , Bigaran Ashley , Fraser Steve , Haykowsky Mark , La Gerche Andre
Published: April 2024

Introduction:
Anthracycline chemotherapy (AC) has been associated with reductions in cardiac function that increases long-term risk of heart failure. We have previously shown that AC is associated with a reduction in cardiopulmonary fitness (VO
2
peak) that occurs alongside a subtle reduction in the heart’s contractile response to exercise. However the degree to which these changes recover following the completion of AC is unknown.
Hypothesis.
We sought to determine whether change in cardiopulmonary fitness (VO
2
peak) and cardiac function persisted at 12-months post-AC completion.

Methods:
28 women with breast cancer who had self-selected to undergo 12-weeks of aerobic and resistance training twice per week during AC (ET; n=14) or usual care during AC (UC; n=14) were followed up at 12-months from AC completion. Prior to AC and at 12-months, participants completed a cardiopulmonary exercise test (VO
2
peak) and cardiac MRI with exercise to assess the stroke volume (SV), heart rate (HR) and cardiac output (CO) response to exercise (measured at rest, and during high-intensity supine cycling).

Results:
Seventeen women (UC: n=8; ET: n=9) have completed follow-up evaluation. AC was associated with reductions in fitness at 12-months in both the UC (22.4±6.8 to 19.1±6.9 ml/kg/min; 15%) and ET (28.5±6.0 to 26.5±5.4 ml/kg/min; 6%, P<0.01), and these declines were not attenuated by ET (interaction, P=0.42). Peak CO was reduce by 13% as compared with pre-AC values (14.0 ± 2.5L/min vs 12.2 ± 2.6 L/min, P<0.01). The reduction in CO was due to a 14% reduction in the SV response to exercise (98.3 ± 12.1 ml vs 84.6 ± 14.5 ml, P<0.01), whereas the HR response was similar (146 ± 16 bpm vs 151 ± 17bpm, P=0.70). No differences were found between resting CO and SV from pre-AC to 12-months (P=0.25 and P=0.27 respectively).

Conclusion:
Cardiopulmonary fitness reductions persisted 12-months following AC-based chemotherapy, which was not attenuated by exercise during AC. Reductions in fitness coincided with reductions in peak cardiac output during exercise.
Abstract 16749: ET
B
Receptor Agonist, IRL-1620, Decreased Cerebral Ischemic Damage by Decreasing Fission and Increasing Fusion of Mitochondria in Rat
Authors: Briyal Seema , Luu Sandra , Gulati Anil
Published: April 2024

Introduction:
We have shown that endothelin B (ET
B
) receptor agonist, IRL-1620, provides neuroprotection by inhibiting apoptosis in rats. Mitochondrial dysfunction has been implicated in the cell death following ischemia.

Hypothesis:
IRL-1620 prevents neuronal death by altering mitochondrial activity.

Methods:
We determined the effect of IRL-1620 on mitochondrial dysfunction following cerebral ischemia. Male Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (MCAO). Following surgery, rats received intravenous injections of vehicle or IRL-1620 (5 μg/kg, i.v.) at 4, 6, and 8 hr post-occlusion on day 0; similar treatment of vehicle or IRL-1620 was repeated on day 3 and 6 post-MCAO. Animals were sacrificed at 24 hr and day 7 following occlusion and brains processed to evaluate expression of mitochondrial dysfunction markers (DRP-1, MFN-2 and ATP5A) using immunofluorescence and western blot.

Results:
Animals treated with IRL-1620 showed significant improvement in all neurological and motor function tests compared with vehicle-treated group. At 24 h and day 7 following MCAO, a significant increase in DRP-1 (a key mediator of mitochondrial fission) and decrease in MFN-2 (key mediator of mitochondrial fusion) was observed in the vehicle-treated group compared to sham group. IRL-1620 treatment significantly [F(5,18)=10.5, p<0.001] decreased (-53%) expression of DRP-1 and significantly [F(5,18)=25.78, p<0.0001] increased (165%) expression of MFN-2 in MCAO rats compared to vehicle treated rats. There were no changes in ATP5A expression levels in the brains of sham, vehicle, and IRL-1620 treated rats 24 h post occlusion. A significant [F(5,18)=11.38, p=0.011] increase (70%) in ATP5A in the vehicle group was observed on day 7 compared to sham. However, IRL-1620 significantly [F(5,18)=11.38, p=0.0009] decreased (-53%) the expression of ATP5A in MCAO rats compared to vehicle. Immunofluorescence studies corroborated Western blot results showing an increase of DRP1 and a decrease of MFN-2 positive cells in the vehicle group after 24 hr and day 7 compared to sham group. These changes were reversed in IRL-1620 treated rats.

Conclusions:
Stimulation of ET
B
receptors with IRL-1620 is neuroprotective in a rat model of cerebral ischemia by decreasing (DRP-1) fission and increasing (MFN-2) fusion of mitochondria.
Abstract 16753: Efficacy & Efficiency of Genome Editing With CRISPR/Cas9 in a Humanized Knock-In Mouse Model of PLN
R14del
Authors: Stillitano Francesca , Raad Nour , Zhang Lu , Fargnoli Anthony , Jeong Dongtak , Ceholski Delaine , Kohlbrenner Erik , Dave Jaydev , Cai Chenleng , Akar Fadi , Hajjar Roger J
Published: April 2024

Introduction:
A mutation in the Phospholamban (PLN) gene, a calcium regulating protein, the Arg14 deletion (R14del), has been identified in patients with atypical Arrhythmogenic Cardiomyopathy (ACM). Carriers of this mutation are at high risk for malignant ventricular arrhythmias and ventricular dilation.

Objective:
To evaluate the efficiency and efficacy of genome editing by using CRISPR/Cas9 and a cardiotropic Adeno-Associated Vector (AAV) in a knock-in mouse model expressing the human coding sequence of mutant
PLN
(hPLN
R14del
).

Methods:
We generated wild-type (WT), heterozygous (Het) and double mutant (Mut) humanized mice. We designed a CRISPR-Cas9/gRNA construct which cut around the site encoding R14Del-PLN gene. To check for CRISPR-Cas9 efficiency we used droplet digital (ddPCR) Genome Edit Detection assay that consist of primer pair to amplify the sequence that includes the mutation, and a FAM-labeled probe designed to bind the mutant allele. Heterozygous mice were injected with 2x10
12
vg of AAV9.CRISPR/Cas9/gRNA for inactivation of the R14del allele. Cardiac function and heart morphology were assessed by Magnetic Resonance Imaging (MRI), echocardiography and H&E staining. Ventricular tachycardia (VT) threshold was defined as the pacing frequency (f
Pacing
) required for induction of sustained VT in ex vivo set-up.

Results:
Echocardiography and histology showed no significant changes in cardiac function and structure in the R14del Het & Mut mice. Eight weeks after AAV injection the hearts were harvested and analyzed for indel frequencies at on-target site in the genome. ddPCR analysis showed an efficiency of ~13% inactivation of the R14del mutation in AAV9/CRISPR-Cas9 injected mice compared to controls. Seventy-five percent of Het hearts exhibited adrenergic mediated VT (f
Pacing
= 19.6±4.7Hz) vs. only 30% of their WT counterparts (25.8±1.4Hz, p<0.05). VT susceptibility in Het hearts was significantly suppressed by AAV-mediated CRISPR/Cas9 delivery targeting the mutant allele.

Conclusions:
Our results demonstrate that mouse model harboring the human R14del mutation does not result in gross cardiac morphological changes. Silencing this mutation by CRISPR/Cas9 AAV based gene therapy reversed the VT susceptibility in the Het mice.
Abstract 16771: Patient Selection for Therapies to Prevent Major Adverse Limb Events
Authors: Bonaca Marc P , Giugliano Robert P , Nault Patrice , Scirica Bejamin M , Pedersen Terje R , Bhatt Deepak L , Keech Anthony C , Storey Robert F , Steg P. Gabriel , Cohen Marc , Goodrich Erica M , Murphy Sabina A , Sabatine Marc S , Morrow David A
Published: April 2024

Introduction:
Recently medical therapies have shown benefit in reducing major adverse limb events (MALE) including acute limb ischemia (ALI), urgent revascularization for ischemia, and ischemic amputation in patients with atherosclerotic vascular disease. Defining predictors of MALE may facilitate patient selection for application of novel therapies.

Hypothesis:
Clinical characteristics can be used to develop a risk score that will predict MALE

Methods:
Clinical characteristics independently predictive of ALI were identified among 3,985 patients with PAD randomized to placebo in TRA 2°P-TIMI 50 and were used to develop a risk score (c-statistic 0.82). This score was prospectively validated in 7,053 and 13,723 placebo patients from the PEGASUS-TIMI 54 and FOURIER trials respectively. Risk in each trial was evaluated stratified by the investigational treatment (vorapaxar, ticagrelor, or evolocumab).

Results:
In the broad PAD placebo population of TRA 2°P-TIMI 50, seven independent predictors of ALI with relative risks ranging from 1.69 to ~10 fold were identified including claudication, prior peripheral revascularization or amputation, ankle brachial index ≤ 0.5, heart failure, low body weight, elevated CRP and ASA monotherapy and assigned a point score.There was a gradient of MALE risk in placebo treated patients from 0.1% to 19.7% with increasing score (p<0.0001; Figure, Top). When validated in PEGASUS-TIMI 54 and FOURIER, discrimination remained high (c-statistic of 0.81 in both datasets). A risk of 4 generally correlated to an annualized risk of MALE of ~ 1% (1.1% TRA2P-TIMI 50, 0.93% PEGASUS-TIMI 54, 1.2% FOURIER). A score <4 identified patients at low risk of MALE, whereas those with a score ≥ 4 had greater baseline risk and benefit of randomized therapy (Figure, Bottom).

Conclusions:
A simple risk score can identify patients at greater risk of MALE who derive greater absolute reductions with effective therapies.
Abstract 16774: Pericardial Inflammatory Burden is Lower in Women With Recurrent Pericarditis
Authors: Ala Chandra K , Banerjee Kinjal , Sato Kimi , Verma Beni R , Anumandla Anil , Kumar Arnav , Afonso Luis C , Jellis Christine , Hachamovitch Rory , Klein Allan L
Published: April 2024

Introduction:
Men with pericarditis are admitted twice as more frequently, but women tend to have more complications. Autoimmune disease is more common in women but its impact on the natural history of pericarditis is unknown. Active pericardial inflammation has been quantified using delayed hyperenhancement (DHE) on cardiac magnetic resonance (CMR) imaging but gender differences have not been studied.

Hypothesis:
We hypothesize that women presenting with recurrent pericarditis have a higher rate of autoimmune etiology. Further, lower admission rates in women may be explained by lower levels of pericardial inflammation.

Methods:
We included consecutive patients with recurrent pericarditis attending the pericarditis clinic at our institution, who underwent echocardiographic and CMR imaging. Clinical features, etiology, laboratory values including erythrocyte sedimentation rate (ESR) and ultrasensitive C-reactive protein (CRP) were obtained. Echocardiographic and CMR findings including effusion, quantitative and qualitative pericardial DHE were analyzed. DHE was quantified on the short-axis fat suppressed contrast enhanced sequences by contouring the pericardium, measuring the pericardial signal that was more than 6 standard deviations above that of normal septal myocardium taken as the reference.

Results:
A total of 198 patients were included, with a mean age of 46±14 years and 103 (52%) females. Women were older than men (49±14 vs. 43±14 years, p = 0.002). Women had a higher prevalence of auto-immune diseases (23% vs. 11%, p = 0.017). On presentation, women more frequently had pedal edema and shortness of breath. Women also had higher ESR (median (IQR) 8 (5-17) vs. 5 (3 - 11) mm, p = 0.007), but CRP was not significantly different. There was no difference in pericardial thickening or effusion on echocardiography. However, on CMR, women were found to have lower DHE (median (IQR) 40 (26 - 62) vs. 53 (35 - 88) cm
3
, p = 0.018). There was no difference in time to resolution between genders (median 21.4 vs. 18.9 months, p = 0.28).

Conclusions:
Autoimmune diseases are a more frequent etiology for women with recurrent pericarditis. Women had less severe pericardial inflammation by DHE. However, the time to resolution was not different.
Abstract 16786: ADP Ribosylation Factor 6 Modulates the Cell Surface Expression of the Acetylcholine Activated Inward Rectifier Potassium Current
Authors: Reiser Michelle , Chidipi Bojjibabu , Noujaim Sami
Published: April 2024

Introduction:
The ADP ribosylation factor 6 (Arf6), a GTP binding protein, is suggested to play a role in the trafficking of potassium inward rectifiers. We investigated the effects of Arf6 on the cell surface expression of Kir3.1 and Kir3.4, the molecular correlates of the acetylcholine activated inward rectifier potassium current (I
KACh
).

Hypothesis:
The GDP and GTP bound forms of Arf6 modulate the surface expression of I
KACh
proteins.

Methods:
We used human embryonic kidney cells stably expressing Kir3.1 and Kir3.4 (GIRK cells). Cell surface I
KACh
proteins were labeled with TertiapinQ ATTO488, visualized with confocal microscopy, or quantified using flow cytometry in the GIRK cells transiently transfected with Arf6WT (wild type), dominant negative Arf6T44N (GDP bound), or constitutively active Arf6Q67L(GTP bound). Patch clamp was used to quantify the effects of Arf6 on the barium sensitive I
KACh
current, and coimmunoprecipitation in human atrial tissue was used to probe the interaction between Kir3.1, Kir3.4 and Arf6.

Results:
In confocal microscopy, Arf6WT, and Arf6T44N localized mainly to the cell membrane, while Arf6Q67L localized to intracellular vesicles. In flow cytometry, Arf6T44N significantly decreased channels expression at the cell surface compared to Arf6WT. Arf6Q67L did not affect cell surface expression compared to Arf6WT. Patch clamp showed that I
KACh
current density was significantly smaller in Arf6T44N compared to WT and Q67L, consistent with the flow cytometry experiment. Kir3.1, Kir3.4 and Arf6 coimmunoprecipitated in whole cell lysates form human atrial tissue samples.

Conclusion:
Expression of the I
KACh
proteins at the cellular membrane is in part modulated by an Arf6-dependent pathway. Constitutive interference with Arf6 cycling between GDP- and GTP-bound forms leads to changes in the cell surface expression of the I
KACh
proteins.
Abstract 16840: A Community Engagement Initiative Supporting a Culture of Heart Health
Authors: Jakubisin Konicki Annette
Published: April 2024

Background:
Historically seen as a man’s disease, coronary heart disease (CHD) is the annual cause of death for approximately the same number of women as men. Strides have been made in raising awareness of women’s CHD risk, and national initiatives call for programs that both raise awareness and sustain engagement in heart healthy lifestyles. A gap remains between women’s personal awareness of risk and the preventative activities in which they engage.

Purpose/Methods:
Embracing the concept of cardiovascular health (CVH) from the American Heart Association’s Impact Goal, a coalition of community organizations partnered to launch a three pronged community engagement initiative (CEI):
Follow the Fifty: Models of Heart Health
. The purpose was to: raise women’s awareness of their risks for CHD; raise women’s CVH awareness, and increase women’s knowledge of evidence based activities that promote and support a culture of heart health through reducing cardiovascular risk factors (CVRF). Women participants (N=177), recruited through community advertising, became “Models of Heart Health.” The nine month CEI provided presentations on stress reduction, CVD awareness, and CVRF reduction activities; community gardens for growing heart healthy foods; and coaches paired with Models to support reducing individual CVRF. Community businesses provided CVH options: heart healthy menu choices, gym classes/memberships, group training activities. Baseline biometric data screened Models for participation (weight, BMI, blood pressure, glucose, smoking status). Models completed self-report surveys describing nutrition, physical activity, and stress management behavior changes resulting from the CEI. Focus groups were held to gather qualitative feedback.

Results/Conclusions:
Follow the Fifty
CEI successfully raised women’s awareness of their risk for CVD and influenced personal behavior change to reduce CVRF, thereby promoting and sustaining heart health. Models reported adopting improved diet (93.6%), physical activity (84.6%), and stress management activities (52.5%). Focus groups identified themes of: “goal driven with accountability,” “ongoing process,” “being rewarded,” a sense of “sisterhood/enduring friendships,” “empowerment,” and “confidence to attain goals.” Providing women with a mechanism for decision support and self-management, while identifying and strengthening the link to community resources resulted in adoption of effective therapeutic CVD preventive behaviors, creating a culture of heart health.
Abstract 16844: Relative Endothelial Toxicity of Tobacco Smoke and E-Cigarette Aerosol: A Functional and Mechanistic Assessment
Authors: Mohammadi Leila , Derakhshandeh Ronak , Han Daniel D , Whitlatch Adam , Huang Abel , Schick Suzaynn F , Springer Matthew L
Published: April 2024

Background:
Smoking cigarettes decreases expression of eNOS in the endothelium, resulting in lower nitric oxide (NO) secretion and decreased flow-mediated dilation in the conducting arteries. In contrast, the effects of e-cigarettes (e-cigs) on endothelial function are just beginning to be studied and the mechanisms of action are unclear.

Aim:
To test the hypothesis that circulating factors from e-cigarette users decrease endothelial eNOS protein levels and NO secretion in primary endothelial cell cultures, relative to nonsmokers and cigarette smokers.

Methods:
36 healthy individuals were recruited and grouped as nonsmokers (n=12), cigarette smokers (n=7), and e-cig users (n=17). Human umbilical vein endothelial cells (HUVECs) were cultured at 20,000 cells per well in 24-well culture plate. Serum samples from individual subjects and endothelial growth media were added at a 1:1 ratio to confluent cells and incubated for 12 hours (basal condition), followed by fresh medium containing VEGF at 50 ng/ml for 30 min (stimulated condition). The amount of NO liberated from cells was measured in culture supernatants by the chemilumin- escence method using a NO analyzer. Endothelial NO synthase (eNOS) protein levels in HUVECs was measured in cell lysates by ELISA. NO and eNOS results were normalized to cell number.

Results:
The cells treated with serum from e-cig users vs. nonsmokers produced less NO upon stimulation (P<.03) and contained less eNOS protein (P<.03). eNOS protein level was lower in the e-cig user serum group than in the cigarette smoker serum group (P<.05), although stimulated NO production was decreased less by e-cig user serum than by smoker serum. Lower eNOS levels in the cigarette group vs. non-smoker group was not significant, but stimulated NO was significantly lower in the cigarette group vs. nonsmoker (P<.006; see figure).

Conclusion:
Exposure of cultured endothelial cells to circulating factors from e-cig users, relative to non-users, leads to lower eNOS protein levels and decreased NO production.
Abstract 16868: Predicted Heart Mass and Organ Offer Turn-Down in Heart Transplant
Authors: Benck Lillian , Kransdorf Evan , Kittleson Michelle , Chung Joshua , Esmailian Fardad , Kobashigawa Jon A
Published: April 2024

Introduction:
Size mismatch is a frequent reason for organ offer turn-down in heart transplantation (HT). While weight is frequently used as the metric for size matching in HT, several recent studies have shown that predicted heart mass (PHM) is a better predictor of mortality. Here, we sought to assess the potential impact of utilizing PHM for size matching.

Methods:
A data set of all potential transplant recipients from January 1, 2007 to December 31, 2016 was obtained from the United Network for Organ Sharing. For each recipient, offers turned-down for donor size/weight were selected. Donor-recipient ratio of PHM was calculated for each donor-potential recipient pair and a value of 0.85 or higher was considered adequate as determined by previous survival modeling. Distribution of PHM for offers turned-down and accepted according to sex mismatch category was assessed. Mean PHM for each sex mismatch category was compared.

Results:
There were 18,251 recipients in the study cohort who received 639,247 offers. Of these, 96,043 (15%) were turned down for donor size/weight. Of offers turned down, mean PHM ratio differed significantly between sex-mismatch categories. Mean donor to recipient PHM ratio was 0.75 for female donor/male potential recipient, 0.98 for female donor/female potential recipient, 0.92 for male donor/male potential recipient and 1.36 for male donor/female potential recipient pairs (p < 0.001) The percentage of offers turned-down for donor size/weight (Figure 1) but with an adequate PHM ratio (solid line) ranged from 98% for male donors/female potential recipients to 19% for female donors/male potential recipients.

Conclusion:
Utilizing PHM for assessment of donor-recipient size match shows that a large number of donors turned down for size would likely be an adequate size match. Thus, the use of PHM has the potential to increase donor heart utilization.
Abstract 16881: Role of Neurohormonal Blockade During Anthracycline Therapy: A Meta-Analysis of 14 Randomized Controlled Trials
Authors: Nandar Phoo Pwint , Myint Phyo Thazin , Swe Khine Mon , Vallakati Ajay
Published: April 2024

Introduction:
Cardiotoxicity is a well-known dose-limiting adverse effect of anthracyclines. The cardio-protective role of the neurohormonal blockade (beta-blocker and/or renin-angiotensin-aldosterone antagonists) in patients receiving anthracycline chemotherapy has been demonstrated, but not consistently in all studies. We performed a systematic review and meta-analysis to evaluate the efficacy of the neurohormonal blockade (NB) for primary prevention of anthracycline-mediated left ventricular (LV) dysfunction.

Method:
We searched PubMed and Cochrane databases for all studies comparing the effects of neurohormonal antagonists with placebo on LV ejection fraction (LVEF) in the patients receiving anthracycline chemotherapy. We included randomized controlled trials with a follow-up duration of ≥ 6 months. The primary outcome was the change in left ventricular ejection fraction (ΔLVEF). Random effects model with inverse variance method was used to analyze the outcomes. Exploratory subgroup analysis based on the type of NB was performed.

Results:
We identified 14 studies (n = 1184) which reported ΔLVEF. Pooled analysis revealed that there was a significantly smaller decline in LVEF (weighted mean difference (WMD), 5.38 (95% CI: 2.52 - 8.23, P =0.0002) in the patients who received prophylactic neurohormonal antagonists compared to placebo. Subgroup analysis showed that both beta-blockers (WMD, 4.26 (91% CI: 1.41-7.11), P=0.003) and renin-angiotensin-aldosterone antagonists (WMD, 6.59 96% CI: 1.40-11.78, P = 0.01) were associated with a smaller decline in LVEF.

Conclusion:
Prophylactic NB attenuates the development of LV dysfunction in patients receiving anthracycline chemotherapy. Studies evaluating the effect on mortality are still required.
Abstract 16892: Cold Exposure Induces Drp1-Mediated Mitochondrial Elongation in Cardiomyocytes and is Associated With Sustained Respiratory Suppression
Authors: Taylor David , Marek-Iannucci Stefanie , Gottlieb Roberta A
Published: April 2024

Introduction:
The effects of cold exposure on the heart are poorly understood. Cardiac hypothermia arises exclusively in the context of coincident ischemia, either in out-of-hospital cardiac arrest, or in the setting of cardiac surgery. Our lab has recently described an intraoperative increase in mitochondrial protein expression in atria of patients undergoing coronary artery bypass graft surgery. We have been exploring the role of cold stimulus as a potential trigger for mitochondrial remodeling.

Methods:
The effects of cold exposure on mitochondrial morphology, fusion/fission protein expression and respiration were assessed in H9C2 cardiomyocytes and the Langendorff-perfused rat heart.

Results:
H9C2 cardiomyocytes were exposed to a range of hypothermic temperatures (25-32°C) under normoxic conditions for up to 24 hrs. Immunofluorescence imaging revealed elongated mitochondria under hypothermic conditions, which was associated with decreased levels of active pDrp1 (Ser616) and its receptor mitochondrial fission factor (MFF). Seahorse respirometry (conducted at 37°C) revealed depression of oxygen consumption in cells previously exposed to hypothermic temperatures. Both morphological and respiratory phenomena persisted when cells were rewarmed to 37°C for 2 hours. In Drp1 siRNA-treated H9C2 cardiomyocytes, mitochondria exhibited elongated morphology as well as depression of oxygen consumption. In Langendorff perfused rat hearts, 1 hour normoxic perfusion at 28 or 32°C gave rise to a reduction in pDrp1(Ser616). Furthermore, reductions in pDrp1 levels persisted following a subsequent 1 hour rewarming at 37°C.

Conclusions:
Hypothermia promoted elongation of cardiac mitochondria via reduced fission activity of Drp1, which was also associated with suppression of cellular oxygen consumption. The presence of mitochondrial elongation and suppressed oxygen consumption in Drp1 siRNA-treated cells suggests a link between Drp1 activity and respiratory function. In cardiomyocytes and Langendorff-perfused hearts, cold-induced Drp1 inhibition persisted following rewarming, suggesting that hypothermia may sustainably inhibit Drp1 activity.
Abstract 16893: The Effect of a Nurse-Driven Program Utilizing Implantable Pulmonary Artery Pressure Monitoring to Reduce Hospitalizations in Low-Socioeconomic Urban Patients With Heart Failure
Authors: Alcain Charina F , Aziz-Smith Rahmana , Chua Rhys , Tabit Corey , Spencer Kirk
Published: April 2024

Background:
The hospitalization rate in patients with heart failure (HF) remains high despite advances in HF treatment. This is especially true in low-socioeconomic urban patients. While implantable pulmonary artery pressure monitors (such as the Abbott CardioMEMS) have been shown to reduce readmissions in highly-selected, overwhelmingly white and male cohorts, their efficacy in low-socioeconomic, urban, minority populations is not known. We hypothesized that a nurse-driven program utilizing the CardioMEMS device in addition to guideline-directed medical therapy could reduce hospitalizations in such patients with heart failure.

Methods:
At the University of Chicago Medical Center, 18 high-utilizing patients (84% non-white, 44% female) with NYHA Class III HF were implanted with a CardioMEMS following a hospital admission for HF. Data obtained from the CardioMEMS guided a specially-trained nurse in adjusting medications in order to relieve or prevent congestion. Enrolled patients were matched using 30 clinical and demographic variables with contemporaneous control patients with HF who received usual care. All patients had been followed at our center for at least 6 months and continued to receive well-established HF management including education, discharge phone calls, close clinic follow up, and use of evidence-based HF medications throughout the study period. Each patient’s hospitalizations were recorded and compared using Fisher’s exact test.

Results:
Among the 18 patients who received a CardioMEMS, there were 33 HF-related hospital admissions during the 6 months prior to CardioMEMS implantation. In comparison, there were 5 HF-related hospital admissions in the 6 months post-implantation, representing an 85% decrease in HF-related hospital readmission (p<0.01). Additionally, 14 out of the 18 patients did not have any HF-related hospital admissions after device implant. Similarly, there were 35 all-cause admissions in the 6 months prior to implantation and only 18 admissions in the 6 months after implantation, a decrease of 49% (p<0.01). Control patients had no significant change in HF-related or all-cause hospitalization.

Conclusion:
A nurse-driven CardioMEMS program significantly reduces HF-related and all-cause hospitalization rates among high-risk, low-socioeconomic, urban patients. Such a program can be used as an effective adjunct to other multidisciplinary interventions in this highly-vulnerable patient population.