bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19365: Serial Changes in ST2 are Superior to Other Biomarkers in the Prediction of Adverse Events in a Cohort of Ambulatory Chronic Heart Failure Patients
Authors: Saenger Amy K , Miller Wayne L , Lueke Alan J , Grill Diane E , Jaffe Allan S
Published: April 2024

Background:
Disease progression in heart failure (HF) reflects multiple neurohormonal derangements resulting in adverse prognosis in the absence of overt clinical events. ST2 is up-regulated in response to cardiac injury/hemodynamic stress while modulating cardiac remodeling via inflammatory and apoptotic pathways. Accordingly, we evaluated changes in ST2 over time in conjunction with troponin T (cTnT) and BNP in ambulatory patients with chronic HF.

Methods:
A cohort of 191 NYHA class III-IV HF patients was prospectively evaluated with serial specimens collected every 3 months over a 2-year period. Primary end points were death or cardiac transplantation; secondary end points were combined death/transplantation and HF-related hospitalization. Plasma ST2 (Critical Diagnostics) was evaluated against contemporary cTnT (Roche 4th generation) and BNP (Shinogi) assays. Gender specific cut-points (>49.3 and >33.5 ng/mL for males and females, respectively) and a clinically defined optimal cut-point for ST2 (>35 ng/mL) were evaluated.

Results:
Time-dependent analyses (dichotomous and continuous variable) demonstrated ST2 gender specific cut-points were superior to a single ST2 cut-point and associated with an increased risk of death or transplantation (HR 4.8, 95% CI 2.8 to 8.3, p<0.0001) and combined death/transplantation/HF-hospitalization (HR 2.1, 95% CI 1.7 to 2.5, p<0.0001). Although cTnT remained the strongest predictor of death/transplantation (HR 3.2, 95% CI 1.6 to 5.4, p<0.0001) in multivariate analyses adjusted for cTnT and BNP, ST2 (HR 3.0, 95% CI 1.6 to 5.4, p=0.0003) added significantly to predictive accuracy. Furthermore, elevated ST2 was the only independent predictor of HF-hospitalization (HR 1.7, 95% CI 1.4 to 2.1, p<0.0001). In these models BNP was no longer significantly predictive (HR 1.2, 95% CI 0.7 to 2.2, p=0.58).

Conclusions:
Serial monitoring of changes in ST2 using gender specific cut-points adds to the diagnostic ability of cTnT in predicting mortality and/or transplantation in outpatients with chronic HF. ST2 uniquely predicts HF-hospitalization/death/transplantation, suggesting a serial monitoring strategy with cTnT and ST2 will optimize identification of HF patients at increased risk for events.
Abstract 19384: Catheter Ablation of Scar-Based Ventricular Tachycardia: Impact of Procedural Duration on Outcomes
Authors: Tung Roderick , Yu Ricky , Hayase Justin , Boyle Noel , Shivkumar Kalyanam
Published: April 2024

Background:
The relationship of procedural duration with efficacy and complication rate in ventricular tachycardia (VT) ablation has not been well studied. The aim of this report is to examine the relationship between procedural duration and VT ablation outcomes.

Methods:
All patients referred for VT ablation between 6/04-6/11 were included in the present study. Procedural duration was defined as the time from the insertion of catheter sheaths through the femoral vein to the time of their withdrawal. Variables that were recorded and analyzed for relationship to procedural duration included: number of induced VTs, in-hospital mortality, and 6-month outcomes.

Results:
148 patients with scar-mediated VT were available for analysis. The mean procedural duration for cases with endocardial, epicardial, and combined epicardial-endocardial VT mapping were: 5.1 ± 1.7, 5.0 ± 1.6, and 6.4 ± 1.7 hours, respectively. Longer procedural duration was associated with a greater number of VT morphologies induced (range 1.5- 3.7 mean VTs induced). The six month freedom from VT for the overall cohort was 53% (ICM=66% (49/74), NICM=39% (27/69)). The duration of the procedure did not impact success rates. An increase in in-hospital mortality was observed for procedures longer than eight hours.

Conclusion:
While longer procedural duration was associated with comparable 6 month freedom from VT recurrence, an escalating risk for in-hospital mortality was seen in patients who underwent procedures longer than eight hours.
Abstract 19410: Myocardial-Specific Overexpression of a Dominant-Negative Mutant of NADPH Oxidase Subunit p67
phox
Attenuates Constitutively Active α&rtf-inf-start;1B&rtf-inf-end;-Adrenergic Receptor-Induced Cardiac Hypertrophy in Transgenic Mice
Authors: Zhao Qiong , Zhao Guiqing , Zhang Chongxu , Xiao Lei
Published: April 2024

Transgenic (Tg) mice with cardiac-specific overexpression of a constitutively active mutant (CAM) α
1B
-adrenergic receptor (AR) was reported to induce cardiac hypertrophy. We had reported a Tg mouse model with cardiac-specific overexpression of a dominant-negative (DN) mutant (V204A) of NADPH oxidase (NOX) subunit p67
phox
that inhibits NOX activity. To test the role of NOX in α
1B
-AR induced cardiac hypertrophy
in vivo
, these two Tg mice were crossed to generate Tg mice with cardiac-specific overexpression of both CAM-α
1B
-AR (A1B) and DN-p67
phox
(DNp67) transgenes. Age (12-week), gender, and body weight-matched mice from the following 4 groups (12 mice/group, each gender): wild type (WT), A1B, A1B/DNp67 & DNp67 were subjected to 2-D echocardiography (echo) to determine the following parameters: left ventricular myocardial area (LVMA), LV wall thickness at end diastole, LV ejection fraction (EF), and LV mass. The LVEF (mean 46-54%) was not statistically different among all groups. DNp67 mice showed no significant difference in LVMA, LV mass & wall thickness vs. WT (Table 1). The A1B mice showed significant increase (
p
<0.05) in LVMA, LV mass & wall thickness indicating LV hypertrophy vs. WT; whereas the A1B/DNp67 mice showed significantly (
p
<0.05) decreased hypertrophy vs. A1B mice but statistically no difference from the DNp67 mice. These data suggested that A1B-induced LV hypertrophy was attenuated in the A1B/DNp67 dual Tg mice. The hearts of the above mice were then harvested after echo, and their mRNA expression of fetal genes including ANF, skeletal alpha actin, β-MHC, and 4 fibrosis genes (no difference among 4 groups, n=3) was quantified using real-time RT-PCR. All the above 3 fetal genes were significantly increased in the A1B hearts vs. WT, and were all significantly (n=4,
p
<0.05) attenuated in the A1B/DNp67 mice. In summary, our results showed that selective inhibition of myocardial NOX subunit p67
phox
attenuated α
1B
-AR-induced cardiac hypertrophy in Tg mice. .
Abstract 19458: Prevalence of Neoplastic and Non-Neoplastic Incidental Findings as Detected by Computed Tomography in Severe Aortic Stenosis: Single Center PARTNER Trial Data
Authors: Doctor Niraj S , Jilaihawi Hasan S , Tarun Chakravarty , Asim Rafiq , Contreras Lauren A , Jasminka Stegic , Kashif Mohammad , Aik Doumanian , Mitch Gheorghiu , Mamoo Nakamura , Friede Gerald , Makkar Raj
Published: April 2024

Background:
In the emerging era of Trans catheter aortic valve replacement (TAVR), CT is important tool for precise screening and procedural outcomes. Non cardiac incidental findings of malignancy are an important clinical concern.

Methods and results:
We retrospectively evaluated the findings from 64-slice screening CT scans performed on 318 patients with severe aortic stenosis (AS) prior to evaluation forTAVR. A total of 235 patients received contrast imaging. Detailed analysis of cardiac and non cardiac structures revealed presence of lung cancer in 10 patients (3%) and Bronchogenic carcinoma in 5 patients (2%), breast cancer in 9 patients (3%), 4 patients with colon cancer (1%) and 4 with lymphoma(1%), 2 with prostate cancer and 1 with renal cell carcinoma and multiple myeloma(1%).

Conclusions:
CT is important factor in patient selection for TAVR but reporting of non-cardiac findings must be meticulous. There is a significant proportion of patients with the incidental finding of Neoplasia.
Abstract 19485: Migrant South Asian Women Have Increased Arterial Stiffness Compared to Black and White Women Residing in the United States
Authors: Eapen Danny J , Manocha Pankaj , Patel Riyaz , Khan Shafaat Ali , Menon Vivek , Al Kassem Hatem , Hammadah Mohammad , Samman Tahhan Ayman , Ghasemzadeh Nima , Khayata Mohamed , Kabbany Mohammad Tarek , Asfari Mohammad , Mohamed Amr Mohamed Rashed , Khuram Ashraf , Bhatia Neal , Bellam Naveen , Sher Salman , Janjua Uzair , Shah Meera , Liu Ying X , Sperling Laurence , Quyyumi Arshed
Published: April 2024

Introduction:
Death from cardiovascular disease (CVD) is proportionally higher in Black and South Asians (SA) residing in the United States (U.S.) compared to their White counterparts. While all other sex- ethnic groups demonstrated a decline in all cause and CVD mortality, it has recently been shown that Asian Indian women residing in the U.S. experienced an increase. Arterial Stiffness indices, such as Augmentation Index, have been associated with CVD in western populations. We hypothesized that, in a community setting, migrant SA Women in the U.S. have a greater degree of arterial stiffness than do their Black (BW) and White Women (WW) counterparts.

Methods:
We studied 697 volunteers residing in the metro Atlanta area from 2006-2010 that include 263 SA women (age 49±12 years), 140 BW (age 46±10 years), and 294 WW (age 48±10 years). Using radial artery tonometry (Sphygmocor©, Atcor) we calculated Augmentation Index Adjusted for heart rate (AIX) as a surrogate measure of arterial stiffness. Anthropometric, clinical and lipid levels were assessed. Women were studied as a whole and a subset of women free of traditional CVD risk factors were analyzed separately. Univariate and multivariate regression models adjusted for age, race, BMI, hypertension, diabetes, dyslipidemia, smoking status, and lipid levels were performed.

Results:
SA women had a greater AIX compared to their BW and WW counterparts respectively (32 vs 25 vs 23, p<0.001). BMI was lowest in SA Women followed by WW and BW respectively (26.7 vs 26.8 vs 31.7, p<0.001). There was a similar amount of hypertension (18%) and dyslipidemia (6%) in SA women but more diabetes (23%) compared to WW (17%, 22%, 5%) and BW (29%, 16%, 6%) (p<0.001 for all). In the subset of women free of CVD risk factors, SA women still had a greater degree of arterial stiffness compared to their BW and WW counterparts (31 vs 24 vs 22, p<0.001). In the entire cohort and in the subset of women free of traditional CVD risk factors, LDL, age and race (p<0.001 for both groups) were significant independent predictors of AIX.

Conclusions:
Community dwelling migrant SA women have a significantly greater degree of arterial stiffness compared to their WW and BW counterparts despite having similar traditional CVD risk factors.
Abstract 19513: Action Potential Prolongation and Heart Failure in an Inducible Mouse Model of Timothy Syndrome 2
Authors: Bett Glenna C , Fernandez Stanley , Nayeri Albert , Lis Agniezka , Fallavollita James , Rasmusson Randall L
Published: April 2024

Introduction:
Timothy syndrome (TS) is caused by a de novo gain of function missense glycine to arginine mutation (G406R) in both the 8 and 8a human splice variants of the Cav1.2 channel (TS1 and TS2 respectively).

Hypothesis:
TS mice will exhibit prolongation of the action potential and will develop heart failure due to calcium overload.

Methods:
Normal expression of the TS2 as a knock in defect is lethal to mice, but the defect is tolerated when suppressed though transcriptional interference by the NEO promoter (TS2-NEO mouse). By crossing TS2-NEO with a mouse carrying a cardiac-specific tamoxifen-inducible CRE we removed the transcriptional suppression and up-regulated expression of mutant channels. We extracted mRNA from cardiac left ventricle and probed with PCR primers to exons 7 and 9. Individual PCR products were incorporated into plasmid DNA and individual clones were isolated. Only 1 in 56 TS2-NEO colonies expressed mutant channels in heart demonstrating that the NEO cassette suppressed mutant isoforms. With tamoxifen, the ratio of mutant to non-mutant exons increased from 1:34 to 29:72 demonstrating a robust upregulation of the mutant TS2 channel. We performed electrophysiology, EKG analysis, and echocardiography.

Results:
TS2 mice showed a significant increase in QT duration before (33.1±1.8 ms) and after (74.0±5.5 ms) tamoxifen-activation of the mutant (n=5, p<0.01). Echocardiography demonstrated a decrease in ejection fraction from 95±2 to 53±6% (n=9) in activated TS2 mice, indicative of development of heart failure, compared to with 95±1 to 89±7% (n=12) for controls (P<0.0001). At the single myocyte level, action potentials were markedly prolonged, and both fast and slow components of inactivation of the calcium current were slowed. Fast inactivation in TS2 mice was 18.8±2.9ms (n=18) vs. 12.5±1.4 in controls (n=21,p<0.05), and slow inactivation in TS was 98.2±4.4ms vs. 77.6±1.7 ms in controls (p<0.0001).

Conclusion:
TS2 mice have QT prolongation, decreased ejection fraction, and altered calcium channel behavior. Calcium overload through the TS2 mutation can cause a rapid development of heart failure. This emphasizes the critical role of the L-type calcium channel inactivation in the physiology of repolarization and heart disease.
Abstract 19521: Impact of Procedural Complications on Survival in Patients with Severe Aortic Stenosis Treated with Balloon Aortic Valvuloplasty: Results from the BRAVO Study
Authors: Yu Jennifer , Kini Annapoorna , Cohen Mauricio , Sartori Samantha , Baber Usman , Pyo Robert , Kovacic Jason , O'Neill Brian P , Moreno Pedro , Alfonso Carlos E , Pinnelas Rebecca , Varghese Christopher , Kakoulides Socrates , Clarke Avery , Thapi Roja , Roy Swathi , Kim Michael , Mehran Roxana , Dangas George , Sharma Samin K
Published: April 2024

Introduction.
Previous studies have examined the baseline predictors of survival in patients with severe aortic stenosis treated with balloon aortic valvuloplasty (BAV). However, the impact of procedural complications on long-term survival is unknown.

Methods.
Weconducted an independent retrospective review of pts who underwent non-emergent BAV at 2 high volume centers from 2005 to 2011. In-hospital events (bleeding, vascular complications, acute kidney injury [AKI], myocardial infarction, stroke) were adjudicated by an independent Clinical Events Committee. Survival status of all patients was ascertained by the Social Security Death Index. We compared patient survival by the occurrence of in-hospital complications. Cox regression analysis was used to adjust for significant baseline and procedural correlates of survival, in order to determine the incremental impact of in-hospital events on longer-term survival.

Results.
The median follow-up duration among 445 patients post BAV was 288 days. Major bleeding (defined as BARC type ≥ 3), AKI and vascular complications (per VARC definitions) were associated with increased mortality. After adjusting for baseline and procedural variables, AKI remained a strong predictor of mortality (OR 6.9, 95% CI 3.7 - 12.6, p<0.001), major bleeding was associated with a trend for increased mortality (OR 1.5, 95% CI 0.96 - 2.5, p=0.07) and vascular complications were eliminated as a predictor. By Cox methods, anemia, atrial fibrillation/flutter and high creatinine at baseline were also associated with mortality whereas rapid RV pacing and attempted “preclosure” of the access site using a suture-based closure device were associated with improved survival (all p<0.05, Figure).

Conclusion.
Procedural complications, in particular AKI, have significant impact on long term survival after BAV. Dedicated studies are required to examine the impact of strategies to reduce procedural complications on long term patient outcomes.
Abstract 19541: Impaired Calcium Release, Prolonged Action Potentials and Early Afterdepolarizations in Ventricular Myocytes from Mice Harboring a Ryanodine Receptor 2 Loss-of-Function Mutation Associated with Catecholaminergic Polymorphic Ventricular Tachycardia
Authors: Zhao Yan-Ting , Loaiza Randall , Valdivia Carmen R , Alvarado Francisco , Li Cong , Powers Patricia , Valdivia Héctor H
Published: April 2024

Catecholaminergic polymorphic ventricular tachycardia (CPVT) patients harboring the cardiac ryanodine receptor (RyR2) mutation RyR2-A4860G exhibit sympathetically-driven idiopathic ventricular fibrillation without cardiac structural defects. In sharp contrast to other CPVT mutations characterized to date, RyR2-A4860G fails to activate in response to increasing luminal [Ca
2+
] and, when expressed in HEK293 or HL-1 cells, it exhibits attenuated store overload-induced Ca
2+
release. Thus, RyR2-A4860G is the first loss-of-function mutation linked to CPVT, but the arrhythmogenic mechanisms are unknown. We used homologous recombination to generate a mouse harboring the RyR2-A4860G mutation and used isolated ventricular myocytes to investigate the cellular mechanisms by which this mutation generates ventricular arrhythmias. Mice heterozygous for the mutation (RyR2-A4860G
+/-
) display no apparent cardiac structural defects. Whole cell current-clamp combined with confocal Ca
2+
imaging to simultaneously record actions potential (AP) and intracellular Ca
2+
transient ([Ca
2+
]
i
) revealed that AP duration at 90% repolarization (APD
90
) in RyR2-A4860G
+/-
was longer than in WT cardiomyocytes at 1 Hz (209±51
vs.
118±37 ms, n=12 and 7, respectively). As a result of prolonged APs, RyR2-A4860G
+/-
cells exhibited early afterdepolarizations (EADs) at significantly greater frequency than WT (50%
vs
14%, respectively). Ca
2+
imaging of RyR2-A4860G
+/-
cells showed that during the longer APs, Ca
2+
release events are often interspaced between two successive AP-triggered Ca
2+
transients. Since the [Ca
2+
]
i
amplitude in RyR2-A4860G
+/-
cells is significantly lower than in WT (3.5±0.6 , 2.5±0.3, and 2.5±0.2
vs.
3.8±0.3, 4.3±0.5, and 4.4±0.7, at 1, 2 and 3 Hz, respectively), the presence of Ca
2+
release suggests decreased Ca
2+
-dependent inactivation, and subsequent re-activation, of L-type Ca
2+
current during the AP plateau. In conclusion, our results demonstrate that RyR2-A4860G mutation is accompanied by profound impairment of SR Ca
2+
release, which leads to AP prolongation and EADs. This is a novel mechanism of arrhythmias in CPVT, distinct from delayed afterdepolarizations that are commonly detected in all gain-of-function RyR2 mutations.
Abstract 19545: The Association Between Adiposity and Mortality in Patients with Coronary Artery Disease is Modified by Time
Authors: Martin Billie-Jean , De Koning Lawrence , Southern Danielle A , Lewin Adriane M , Galbraith P D , Norris Colleen M , Knudtson Merill L , APPROACH Investigators
Published: April 2024

Introduction:
Obese Coronary Artery Disease (CAD) patients have improved short and intermediate term outcomes compared to those of normal weight. However excess mass may be associated with poor long-term outcomes. The objective of this study was to assess the association between weight and mortality in a population with CAD in different time frames.

Methods:
We used the Alberta Provincial Project for Outcomes Assessment in Coronary Heart Disease (APPROACH) database. Subjects were classified by BMI as normal weight (18.5 - 24.9kg/m2), overweight (25 - 29.9kg/m2), obese class I (30 - 34.9kg/m2), obese class II (35 - 39.9kg/m2), or obese class III (≥40 kg/m2). Mortality was considered over the entire follow-up, within 2 years of catheterization (short-term) or more than 2 years post-catheterization (long-term). Cox models were used to determine the association between weight and mortality. Models were adjusted for all clinical risk factors and initial treatment strategy.

Results:
There were 45494 subjects with ≥ one vessel CAD (overweight: 41.9%, obese class I: 23.8%, obese class II: 7.8%, obese class III: 3.5%; 23.9% female; mean age 64.0 years). There were 7904 deaths over a median of 5.6 years of follow-up (61% after 2 years). In the complete follow-up period, compared to normal weight, the hazard ratio (HR) for mortality among overweight subjects was 0.84 (p<0.0001), obesity class I was 0.91 (p=0.004), obesity class II 0.98 (p=0.61), obesity class III 1.15 (p=0.038). There was a significant interaction between time and each weight class (p<0.0001). In short-term follow-up, the HR for overweight was 0.80 (p<0.001), for obese class I was 0.77 (p<0.001), for obese class II 0.80 (p=0.006) and for obese class III was 0.92 (p=0.434). With deaths in the first two years excluded, only overweight status was associated with reduced mortality, while obese class III was associated with increased mortality (HR 1.31 (95% CI 1.12, 1.54).

Conclusion:
The association of adiposity with mortality in CAD patients varies by time, with the protective effect of excess weight diminishing over time. Conditions that decrease mass may result in early deaths.
Abstract 19546: Retinoblastoma Regulates Cardiac and Mesenchymal Stem Cell Niches during Adult Heart Regeneration
Authors: Hatzistergos Konstantinos E , Williams Adam , Balkan Wayne , Margitich Irene S , Hare Joshua M
Published: April 2024

Introduction:
Cardiac (CSCs) and mesenchymal stem cells (MSCs) stimulate cardiac repair, both primarily and secondarily by stimulating endogenous cardiac regeneration; however, the mechanisms underlying successful cardiac repair remain elusive and controversial. We addressed this issue in a porcine model of cell therapy by quantifying levels of Ser-608 hyperphosphorylated retinoblastoma (Rbser608+), which marks actively regenerating cardiomyocytes (CM) in adult newt hearts, and Ink4aARF (alternate reading frame of Ink4a), which inhibits cell cycle. Hypothesis: Interactions between CSCs and MSCs regulate Rbser608 and Ink4aARF expression in endogenous progenitors and CM to enhance cardiac regeneration.

Methods:
Twenty adult swine underwent myocardial infarction (MI), followed 2 weeks later by intramyocardial injection of 200M human (h)MSCs (n=5), 1M hCSCs (n=5), 200M hMSC plus 1M hCSC (MCC, n=5) or placebo (n=5). Tissue from immunosuppressed animals were analyzed 4 weeks later for exogenous cell engraftment (human Alu). Ink4aARF and Rbser608 were assessed in GATA4+ progenitors and mitotic CMs (phosphoH3+).

Results:
In situ hybridization demonstrated Alu+ cells in all groups. Engraftment was ∼7-fold greater in the MCC group compared to hCSCs or hMSCs (7.8±4.6, 0.2±0.2, 1.4±0.7 Alu+/cm3 respectively, p=0.0003) and infarct size was reduced 2-fold in MCC vs either cell type alone. Interestingly, Rbser608+ was expressed both in porcine GATA4+ progenitors as well as mature CM. There were 3 times as many Rbser608+/GATA4+ progenitors (150M/cm3) in the MCC hearts compared to the other 3 groups (p<0.0001). In addition ∼20% of the CM were Rbser608+/Ink4a(-), suggesting that the MCC hearts contained CM capable of completing the cell-cycle (p<0.0001). There was also a 46-fold increase in mitotic CMs in MCC hearts vs. either cell alone (P<0.0001). Importantly, MCC recipients contained a subpopulation of Ink4aARF(−)/phosphoH3+ CM, supporting the existence of transient amplifying CM with the capacity to undergo multiple cell divisions.

Conclusions:
Together these findings demonstrate a novel mechanism of heart regeneration, where hMSC and hCSC interactions propagate Rbser608 in CM and CSCs to regulate cell-cycle and stem cell fate decisions.
Abstract 19570: A Multigenic Etiology 0f Hypoplastic Left Heart Syndrome: An Analysis Based on Three Novel Mutant Mouse Models of Hyoplastic Left Heart Syndrome
Authors: Liu Xiaoqin , Saeed Shazina , Li You , Francis Richard , Tobita Kimimasa , Kim Andy J , Shung Wendy , Leatherbury Linda , Lo Cecilia W
Published: April 2024

Hypoplastic left heart syndrome (HLHS) is a congenital heart defect characterized by severe hypoplasia of the left ventricle (LV) with aortic and/or mitral valve stenosis. Despite advances in HLHS surgical management, the etiology for HLHS remains unknown. Accumulating evidence supports a genetic etiology for HLHS, but mutant mouse models of HLHS have not been described. We recovered three HLHS mutant mouse models in a large scale recessive mouse mutagenesis screen (Figure). In mutant line 635 named
Ohia
, 2 mutants with HLHS were recovered (Figure). Exome sequencing analysis identified three mutations in each of three genes: prolidase (Pepd), NAD synthetase (Nadsyn1) and protocadherin b9 (Pcdhb9). All three mutations were homozygous and shared in common in the two HLHS mutants, suggesting a multigenic etiology for HLHS in
Ohia
. All 3 genes show parallels with defects seen in HLHS patients. Pepd, which regulates proline recycling and collagen metabolism, may have relevance for the marked collagen reduction seen in the LV of HLHS patients. Nadsyn1, which synthesizes NAD, a coenzyme essential for metabolic redox reactions, is of potential importance, given recent study of HLHS patient heart tissue showed many transcript expression changes associated with oxidative phosphorylation. Pcdhb9, which likely mediates cell-cell adhesion, also may have relevance, given the expression of adherens junction related genes is reported to be markedly changed in HLHS heart tissue. Collectively, these findings suggest mutations affecting energy metabolism/oxidative stress, and cell-cell/cell-matrix interactions may play critical roles in HLHS. Consistent with this, preliminary results from the analysis of the other HLHS mutant mouse lines revealed mutations in other genes with overlapping function, including a collagen gene mutation. These observations suggest HLHS has a multigenic etiology, which may account for its apparent complex genetics. Support by U01-
HL098180
Abstract 19574: Overexpression of Active Katp Channels in Adult Mouse Hearts Leads to Conduction Block and Heart Failure
Authors: Zhang Haixia , Uchida Keita , Guo Qiusha , Chen Feng , Nichols Colin G
Published: April 2024

ATP-sensitive potassium (KATP) channels are hetero-octamers of four inward rectified potassium channel subunits (Kir6.1 or Kir6.2) with four sulfonylurea receptor subunits (SUR1 or SUR2). Cardiac sarcolemmal KATP channels are normally closed by high intracellular ATP concentration and will activate under severe pathological conditions where intracellular ATP depletes. Double transgenic mice overexpressing both ATP-insensitive Kir6.2 [K185Q, ΔN30] and SUR1 have shown arrhythmia and premature death. The premature death prevented further investigation of the underlying mechanism. In the present study, the tamoxifen (Tx)-inducible Cre-ER system was introduced to control timing of Kir6.2 [K185Q, ΔN30] expression. Transgenic mice carrying αMHC-Cre-SUR1 were cross-bred with mice carrying myh6-Cre-ER and Rosa26-Kir6.2 [K185Q, ΔN30] (a loxP-flanked DNA STOP sequence was inserted before Kir6.2 transgene). Adult triple transgenic (TTG) as well as littermate double transgenic (DTG), single transgenic (STG), and wild type (WT) mice were injected with Tx and conscious ECG recordings were monitored daily. Prior to Tx induction, SUR1 overexpressing mice have a prolonged PR interval. Within one week after Tx induction, TTG mice show further PR prolongation progressing to 2° AV block and occasionally AV dissociation. TTG mice also displayed severe bradycardia and morphological changes in the ST segment, which were not observed in littermate DTG, STG or WT mice. Two weeks after Tx induction, TTG mice developed larger hearts (wet heart weight: tibia length of 8.9 vs. 7.7 mg/mm in SUR1 expressing mice, p<0.05) and over half of the TTG mice developed edema throughout the body. TTG mice also showed higher mortality following induction (10 of 23 TTG deaths vs. 1 of 35 in littermates). H & E staining of heart slices revealed larger intercellular volume in TTG but not in littermates. These results suggest that overexpression of both active KATP subunits in adult hearts leads to conduction block, possible alterations in repolarization patterns, heart failure, and higher mortality. This model reiterates and further defines the severe pathology of overactive myocardial KATP channels and now provides the necessary system in which to dissect the mechanistic basis.
Abstract 19599: Loss of Alpha-Catenins Increases Nuclear Yap and Cardiomyocyte Proliferation and Improves Cardiac Function Following Myocardial Infarction
Authors: Li Jifen , Gao Erhe , Goossens Steven , van Roy Frans , Radice Glenn
Published: April 2024

Background:
Shortly after birth, muscle cells of the mammalian heart lose their ability to divide. Thus, they are unable to effectively replace dying cells in the injured heart. The recent discovery that the transcriptional co-activator Yap is necessary and sufficient for cardiomyocyte proliferation has gained considerable attention. However, the upstream regulators that control Yap activity in the heart remain largely unknown. Objective: To investigate the role of α-catenins in the heart using cardiac-specific αE- and αT-catenin double knockout (α-cat DKO) mice.

Methods:
We used two cardiac-specific Cre transgenes to delete both αE-catenin (Ctnna1) and αT-catenin (Ctnna3) genes either in the perinatal or in the adult heart, and performed a series of experiments to examine the role of α-catenins under normal and pathological conditions.

Results:
Postnatal depletion of α-catenins caused a decrease in cardiomyocyte size and an increase in cardiomyocyte number in the α-cat DKO mice. Increased nuclear Yap and the cell cycle regulator cyclin D1 accompanied cardiomyocyte proliferation in the α-cat DKO hearts. In comparison, ablation of α-catenins in the adult heart did not result in a proliferative phenotype. However, inactivation of α-catenins improved cardiac function following myocardial infarction. Increased nuclear Yap along with increased number of cells in cytokinesis indicated that cardiomyocyte proliferation contributed, at least in part, to the improved contractile function in the α-cat DKO heart following injury.

Conclusions:
These studies demonstrate that α-catenins are critical regulators of Yap, a transcriptional co-activator essential for cardiomyocyte proliferation. Furthermore, we provide proof-of-concept that inhibiting α-catenins might be a useful strategy to promote myocardial regeneration following injury.
Abstract 19611: An Examination of Survival by Sex in the HVAD BTT and CAP Trials
Authors: McGee Edwin C , Aaronson Keith , Birks Emma J , Boyce Steven W , Cotts William G , Najjar Samer S , Pagani Francis D , Hathaway David , Jacoski Mary V , Najarian Kevin B , Slaughter Mark S
Published: April 2024

Background:
The HeartWare
®
Ventricular Assist System (HVAD) is a novel design, continuous flow, centrifugal pump. The ADVANCE Bridge to Transplant Trial (BTT) was a multi-center, prospective trial that used an external contemporaneous control group from the Inter-Agency Registry for Mechanically Assisted Circulatory Support (INTERMACS) to compare the HVAD Pump with commercially available left ventricular assist devices (LVAD).

Methods:
Baseline characteristics, adverse events and subsequent survival were compared for men and women in the combined BTT and Continued Access Protocol trials (CAP). Survival was evaluated by Kaplan-Meier and proportional-hazards methodologies.

Results:
In the combined BTT and CAP study (N=332), 236 men and 96 women received an HVAD pump. At baseline, men had larger BSA (2.13+0.26 versus 1.80+0.25,
P
<0.001), more frequent history of hypertension (61.9% versus 49.5%,
P
=0.048) and more ischemic cardiomyopathy (45.3% versus 15.6%,
P
<0.001). Kaplan-Meier analysis revealed no significant difference in survival at 180 days (91.5%, men; 89.6%, women) and 1-year (84.1%, men; 84.3%, women). Furthermore, a Cox proportional hazards model indicated no statistically significant gender effect on survival when controlling baseline BSA. A review of adverse events revealed similar rates between men and women who received an HVAD.

Conclusion:
As expected, heart failure etiology differed between men and women in this BTT cohort. However, these data suggest that gender was not a factor for survival in men and women receiving the HeartWare System, and the survival data in women compares very favorably to data reported using contemporary LVADs.
Abstract 19613: Ventricular Repolarization in Transient Apical And Midventricular Ballooning
Authors: Bonnemeier Hendrik , Sandrock Sarah , Demming Thomas
Published: April 2024

The aim of the present study was to assess potential differences in cardiac repolarization dynamics in patients with transient left ventricular apical ballooning syndrome (AB) and the midventricular variant (MB). Even though repolarization abnormalities and QT interval prolongation in the surface electrocardiogram (ECG) have been consistently reported, repolarization dynamics have not yet been investigated in the AB and MB variants. We hypothesized that differences in regional sympathetic denervation may induce differential effects on cardiac repolarization.

METHODS:
In a prospective single-center study, 49 consecutive patients with transient left ventricular dysfunction syndrome underwent 3-channel-Holter-ECG-recording on the third day after admission. A total of 27 recordings of patients with AB and 10 recordings of patients with MB were valid for beat-to-beat-QT-interval-analyses.

RESULTS:
There were no significant differences in baseline clinical characteristics between AB and MB patients. Patients with MB showed significantly lower values for mean RR interval (835 ± 104 vs. 908 ± 118 ms; P<.05). Both, Bazett- and Fridericia-corrected QT-intervals were significantly longer in MB patients (QTcB 441.9 ± 38 vs. 483.4 ± 40ms; P<.05; QTcF 435.0 ± 36 vs.469.4 ± 36.5 ms; P<.05). Parameters of QT-interval variability (QTSD) and QT-interval dynamicity (QT/RR-slope) also exhibited significant differences between groups (diagram).

CONCLUSION:
There are significant differences in cardiac repolarization between AB and MB syndromes. Patients with MB show more prolonged QT-intervals and a higher degree of heterogeneity of ventricular repolarization. Thus, regional midventricular sympathetic denervation may be associated with even higher arrhythmic risk in transient left ventricular dysfunction syndrome.
Abstract 19684: The Deficiency of β-Arrestin 2 Attenuates Abdominal Aortic Aneurysm Formation in Mice
Authors: Trivedi Darshini , Loftin Charles , Langenbach Robert
Published: April 2024

β-arrestin 2 (βarr2 ) is a multifunctional scaffolding protein that participates in the regulation of numerous signaling pathways by coupling with G-protein coupled receptors, such as the angiotensin II (AngII) receptor AT1a. The aim of the current study was to examine the role βarr2 in AngII-induced abdominal aortic aneurysm (AAA) formation in mice. Male Apoe-/-/βarr2+/+ and Apoe-/-/βarr2-/- mice were infused with AngII (1000 ng/kg/day) or saline (vehicle) for 28 days and analyzed for AAA incidence and severity. AngII induced a 61.8% incidence (21 of 34) of AAAs in Apoe-/-/βarr2+/+ mice, as compared to 9.5% (2 of 21) in Apoe-/-/βarr2-/- mice, indicating the importance of βarr2 in AAA formation. To investigate the mechanisms by which βarr2 contributes to AAAs, we determined the effect of βarr2 deficiency on the expression of the inflammatory mediator cyclooxygenase 2 (COX-2) that we have previously shown to be a key contributor to AngII-induced AAA pathology. AngII induced abundant COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice, whereas COX-2 expression was significantly attenuated in the aortas of Apoe-/-/βarr2-/- mice (P<0.05), indicating that βarr2 is involved in the induction of COX-2 in response to AngII. An extensively studied pathway triggered by the βarr2-AT1a complex is ERK1/2 activation, and pERK1/2-mediated signaling has been independently shown to be important in AAA development. Indeed, activated ERK1/2 was observed in the abdominal aortas of Apoe-/-/βarr2+/+ mice, but not in the abdominal aortas of Apoe-/-/βarr2-/- mice. To determine if ERK1/2 activation was a mechanism for βarr2-AT1a-induced COX-2 expression, Apoe-/-/βarr2+/+ mice were treated with the ERK1/2 inhibitor, CI1040 (100mg/kg), together with AngII and examined for COX-2 expression. ERK1/2 inhibition markedly decreased AngII-induced COX-2 expression in the abdominal aortas of Apoe-/-/βarr2+/+ mice (P<0.05) to a level that was equivalent to the COX-2 expression observed in Apoe-/-/βarr2-/- mice. Thus, βarr2 may contribute to AAA formation by activating the ERK1/2-COX-2 pathway. These studies have important implications for the design of therapeutics that target βarr2-mediated signaling for the treatment of AAAs.
Abstract 19687: The Signaling Pathway for Aldosterone-induced Mitochondrial Production of Superoxide Anion in the Myocardium
Authors: Ennis Irene L , Caldiz Claudia , Villa-Abrille Maria C , Morgan Patricio E , Chiappe de Cingolani Gladys E , Cingolani Horacio E
Published: April 2024

Mineralocorticoid receptor (MR) antagonists decrease morbidity and mortality in heart failure patients for whom oxidative stress is common; however, the underlying mechanism of MR-antagonist protection is unclear. Because aldosterone stimulates reactive oxygen species production, we explored in rat myocardium the effect of aldosterone on O2[[Unable to Display Character: ˙]] production and the intracellular pathway involved. Aldosterone dose-dependently stimulated O2[[Unable to Display Character: ˙]] production. At 10 nmol/L, aldosterone increased O2[[Unable to Display Character: ˙]] to 165±8.8 % of control, an effect prevented by the MR antagonists, eplerenone and spironolactone (107±7.8 and 103±5.3 %, respectively), and by inhibition of EGF receptor (EGFR) with AG1478 (105±8.0%), implicating EGFR transactivation in this pathway. Similar results were obtained silencing MR expression by direct intramyocardial injection of a lentivirus coding for a siRNA against the MR. The aldosterone effect was mimicked by the mKATP channel opener diazoxide but blocked by preventing its opening with 5-HD and glibenclamide, implicating the mitochondria as the O2[[Unable to Display Character: ˙]] source. Inhibiting the respiratory chain with rotenone also cancelled aldosterone-induced O2[[Unable to Display Character: ˙]] production. In addition, the aldosterone effect depended on NADPH oxidase and phosphoinositide 3-kinase activation, as apocynin and wortmannin respectively inhibited it. EGF (0.1µg/mL) similarly increased O2[[Unable to Display Character: ˙]], although in this case MR antagonists had no effect, suggesting that EGFR transactivation occurred downstream from MR. The results allow us to propose that a decrease in oxidative stress may be one of the mechanisms contributing to the beneficial effects of MR antagonists in heart failure.
Abstract 21: Mobile Extracorporeal Life Support for Patients With Refractory Cardiogenic Shock or Reanimation - The Concept of a Regional Supply Network
Authors: Albert Alexander , Born Frank , Kamiya Hiro , Saeed Diyar , Akhyari Payam , Kindgen-Milles Detlef , Lichtenberg Artur
Published: April 2024

Objectives: To prove the concept of a regional supply network for mobile extracorporeal life support (ECLS), provided by an university heart centre, specialised on mechanical support.

Methods: We established a mobile ECLS service for regional catheter laboratories (cath-lab). We included patients with severe refractory cardiogenic shock and/or resuscitation if locally available therapies failed and a safe transport to a heart centre was not possible. Without immediate mechanical support the patients are considered to die. Logistic optimization was achieved by 1) use of a miniaturized ECLS device (Life Box, Sorin), which is 24-hours instantly ready for use, 2) provision of a passenger car with flash lights for going, 3) placement of stickers with the 24 hours emergency numbers on prominent places, 4) training of cardiologists in insertion of femoral ECLS cannulae.

Results: Seven cath-labs joined the supply network. From 08/2011 until 05/2012 mobile ECLS was used in 39 cases (age: 3 to 86 years; mean 58). Distance: 0.5 to 224 km. Resuscitation time: 5 -240 min. All patients received on-site femoral veno-arterial ECLS. Duration of support: 1 to 28 days (mean:8.3). Further treatment include: implantation of a ventricular assist device, cardiac transplantation, coronary artery bypass grafting, left ventricular thrombectomie, PTCA, mitral- and aortic valve replacement. 30-day survival without significant neurological deficits was 44% for men, 50% for women.

Conclusion: Mobile ECLS therapy, using recent technology, offers new options for patients, who are otherwise likely to die. The concept of a regional ECLS supply network ensures an optimized logistic and minimization of loss of time
Abstract 232: Sensitivity of Individual Data Modalities for Detecting Return of Spontaneous Circulation and Rearrest with Defibrillator Data
Authors: Sundermann Matthew , Salcido David D , Menegazzi James J
Published: April 2024

Background

Determining the presence of return of spontaneous circulation (ROSC) and re-arrest (RA) in out-of-hospital cardiac arrests offers a challenge for health care providers and researchers. A better understanding of how different data streams reflect patient vital status could improve patient care by reducing time to identification of ROSC and RA and by improving the efficiency of retrospective analyses. We hypothesized that some data streams in the absence of others may be insufficient in determining rhythm status and we sought to determine the extent of these insufficiencies.

Methods

Defibrillator data for non-traumatic cardiac arrests collected by the Resuscitation Outcomes Consortium’s (ROC) Pittsburgh site from 2006-2008 and 2011 were analyzed. Custom software was used to identify ROSC/RA status during the resuscitation and post-resuscitation phases of EMS treatment. The data streams included audio, force of compression (COMP), transthoracic impedance (IMP) and patient care reports (PCR). Official ROSC/RA status was established using all available channels. We then analyzed each channel for indicators of ROSC/RA at those time-points when ROSC/RA were noted in the initial analysis. Sensitivities and specificities for detecting ROSC/RA were calculated for each channel relative to the clinical benchmark, a combination of ECG +IMP signals in Stata 12.

Results

The ROSC sensitivities for each signal compared to our clinical benchmark were .890(audio), .912(ECG), .934(IMP), .868(COMP) and .813(PCR). ROSC/RA combined sensitivities were calculated to be .851(audio), .900(ECG), .933(IMP), .880(COMP) and .719(PCR). The RA sensitivities were calculated to be .767(audio), .860(ECG), .933(IMP), .833(COMP) and .430(PCR) while specificities were calculated to be 1(audio), 1(ECG), 1 (IMP), 1(COMP) and 0(PCR).

Conclusion

The ECG and IMP individual signals produced the highest sensitivity in detecting ROSC/RA when compared to our benchmark of ECG + IMP. When analyzing a case with just

one signal, the sensitivity for detection of ROSC/RA may be grossly inadequate particularly with only PCR information. However, the most commonly available pairing of data streams in modern defibrillators, ECG and transthoracic impedance, is accurate.
Abstract 248: Continuous Chest Compressions with Interposed Ventilations Are Associated with Improved Outcomes from Suspected Asphyxial Arrest
Authors: Lemieux Justin , Husa Ruchika , Scyoc Dorothy , Gordon James , Sell Rebecca , Chappel Ruth , Minokadeh Anushirvan , Davis Daniel
Published: April 2024

Background: A continuous chest compression (CCC) approach to CPR avoids pauses that decrease coronary perfusion pressure. However, the ability to provide adequate ventilation during CCC remains unclear. Cardiopulmonary arrest (CPA) victims with suspected asphyxia would be expected to be the most impacted by inadequate ventilation during CPR.

Objective: To explore the impact of CCC on outcome from inpatients with suspected asphyxial CPA.

Methods: This study was conducted in two urban university hospitals from 2005-09. The Advanced Resuscitation Training (ART) program was implemented in 2007. The ART program advocates CCC with interposed ventilations performed at a 10:1 ratio. Ventilations are initiated with the onset of compression recoil for both unprotected and protected airways. Data for all CPAs are entered into a resuscitation database. CPA events are categorized based on suspected etiology. Survival-to-discharge rates before and after implementation of the ART protocol were evaluated using chi-square analysis including test for trend. Ventilation rates were measured over the final 18 months of the study.

Results: A total of 140 inpatients had suspected asphyxial CPA during the study period. Survival-to-discharge increased from 21.8% to 47.2% following implementation of the ART CCC protocol (p<0.001). Average ventilation rates associated with CCC were 9.7 breaths/min.

Conclusions: An inpatient CCC protocol with ventilations interposed at a 10:1 ratio was associated with marked improvements in outcome among patients with suspected asphyxial CPA. These data suggest that adequate ventilation can be achieved with synchronous delivery of breaths with the recoil phase of compressions. Controlled ventilation rates were also achieved.
Abstract 250: Effect of a Single First 4 Minutes BLS Training Session on BLS Skills Acquisition and 6-Month Retention for First-Year Medical Students
Authors: Draoua Mehdi , Sinz Elizabeth
Published: April 2024

Introduction
: First 4 Minutes (FFM) incorporates experiential learning and real-time problem solving using simulated emergencies that require individuals to work collaboratively for success. This study examined the effect of a Basic Life Support-based FFM exercise on novice students’ BLS individual and team skill acquisition and retention.

Method
: 41 first year medical students were randomly assigned to teams in one of 2 groups. All participants had completed and passed a standard classroom BLS course including lecture, manikin practice and written exam and manikin-based skills test. The experimental groups then participated in a FFM-BLS training session using a feedback manikin (Laerdal ACS manikin with PC skills reporting software). Students’ BLS skills were compared using the associated computer software on day 1 with and without the FFM-BLS training at baseline and again 6 months later on the same manikin. Individual performance of chest compressions was compared for all participants. Group code response data (time to first AED shock, first shock pause, total hands off time during code, and percent of correct depth of compression) as well as subjective teamwork analysis scores were measured. Statistical analysis was performed using a Signed Rank Test and Wilcoxon Rank Sum Test.

Results
: Initial performance in BLS simulation prior to the FFM-BLS activity was similar. Analysis of individual data both immediately after the BLS course with or without FFM-BLS and at 6 months showed a significantly increased percentage of correct depth of compression (p=0.006 & 0.016) and of average depth (p=0.008 & 0.012) in the FFM-BLS group compared with the control group. Group code response data and teamwork analysis scores were significantly better in the experimental group on day 1 but only showed a trend toward better performance in the experimental group at 6 months in this small sample.

Conclusion
: Supplemental simulation training using the FFM approach is associated with improved acquisition and retention of individual and teamwork BLS skills by first year medical students and should be considered to enhance their acquisition of these skills.