bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18315: Percutaneous Coronary Intervention versus Conservative Therapy for Acute Management of Spontaneous Coronary Artery Dissection
Authors: Tweet Marysia , Hayes Sharonne N , Lerman Amir , Holmes David R , Rihal Charanjit S , Gulati Rajiv
Published: April 2024

Objective:
To evaluate outcomes of acute spontaneous coronary artery dissection (SCAD) managed with percutaneous coronary intervention (PCI) or conservative therapy.

Background:
SCAD is a non-atherosclerotic acute coronary syndrome that typically affects young otherwise healthy females. Whether SCAD with normal vessel flow at presentation should be managed with PCI or conservative therapy remains unknown.

Methods:
We performed a retrospective study of patients after a first SCAD episode (n=142). We excluded those treated with fibrinolysis (n=12) or coronary artery bypass grafting (CABG, n=8). We evaluated in-hospital and late outcomes in three SCAD groups: Vessel occlusion at presentation treated with PCI (Occ-PCI, n=30); normal vessel flow treated with PCI (NF-PCI, n=34) and those managed conservatively (CON, n=58).

Results:
Overall mean age was 42+9 years, 91% were female and 41% presented with STEMI. Outcomes are shown in the table below. In Occ-PCI, technical failure occurred in 8/30 (27%), of whom 5 required emergency CABG with one in-hospital death. Comparing NF-PCI with CON, there were no differences in clinical characteristics. Technical failure occurred in 16/34 (47%) of NF-PCI due to failure to cross with wire/device (8/34) or final loss of flow (8/34). Emergency CABG was required in 5 (15%). In CON, 54/58 had an uneventful in-hospital course. Four (7%) exhibited early dissection progression of whom two received PCI and one CABG. Long-term rates of target vessel revascularization, but not recurrent SCAD, were higher in NF-PCI vs CON (26% vs 9%, p=0.02; 24% vs 14%, p=0.23).

Conclusions:
PCI for acute SCAD is associated with high rates of technical failure and adverse clinical outcomes. In SCAD with normal vessel flow, conservative management may be preferable, with close early observation due to a hazard of progression of dissection. These findings underscore the importance of tailoring therapy to etiology of coronary obstruction.
Abstract 18325: Functional Relationship of the COL4A1/COL4A2 Locus on Chromosome 13q34 to Coronary Artery Disease (CAD)
Authors: Turner Adam , Nikpay Majid , Lau Paulina , Soubeyrand Sebastien , McPherson Ruth
Published: April 2024

Background:
The
COL4A1/COL4A2
locus has been linked to CAD in recent large GWAS meta-analyses. The COL4A1 and COL4A2 proteins constitute the major structural component of basement membranes, have important functional roles in angiogenesis, and mutations have been associated with diverse vascular abnormalities. We performed epistasis analysis for CAD-associated SNPs at the
COL4A1/COL4A2
locus; this revealed genetic interaction with members of the TGFβ/Smad signalling pathway. Furthermore, pathway analysis of GWAS has implicated TGFβ and Smad signaling as well as the extracellular matrix as enriched CAD pathways. Bioinformatic analysis also predicted binding of Smad3 and Smad4 to the promoter region of
COL4A1/COL4A2
. We sought to address the hypothesis that the TGFβ-mediated regulation of
COL4A1
and
COL4A2
is via Smad3/Smad4 and that this pathway is relevant to the pathogenesis of CAD.

Methods and Results:
Under basal conditions, HT-1080 fibroblast cells treated with TGFβ1 for 16h produced 5 fold and 3 fold increases in
COL4A1
and
COL4A2
mRNA respectively as measured by qRT-PCR. In contrast, 16h treatment with TGFβ1 in the presence of the specific Smad pathway inhibitor SB431542 (10nM) abolished
COL4A1/COL4A2
upregulation (p<0.001). To rule out the possibility that TGFβ1 regulates
COL4A1
and
COL4A2
expression indirectly via a non-Smad pathway, we showed that inhibition of the JNK, p38 MAPK, and ERK pathways had no effect on
COL4A1
and
COL4A2
levels basally or in response to TGFβ1. siRNA knockdown (>85%) of
SMAD3
in HT-1080 cells diminished the TGFβ1 upregulation of both
COL4A1
and
COL4A2
mRNA levels in comparison to nontarget siRNA (p<0.001). The effect of TGFβ1 on
COL4A1
and
COL4A2
mRNA expression was completely abolished when
SMAD3
and
SMAD4
were knocked-down in concert. These effects on
COL4A1
and
COL4A2
mRNA expression were recapitulated at the protein level by Western blotting.

Conclusions:
These data suggest that Smad3 and Smad4 are the downstream mediators by which TGFβ1 upregulates COL4A1 and COL4A2 expression in HT-1080 cells. This work further highlights the importance of the extracellular matrix and TGFβ/Smad signalling in the pathogenesis of CAD.
Abstract 18326: Elevated Right Ventricular Operant Diastolic Elastance Strongly Predicts Increased Risk of Mortality Following Heart Transplantation
Authors: Rhee June-Wha , Sudini Naga L , Pham Michael , Fearon William , Lee David , Beygui Ramin E , Montoya Jose G , Wu Joseph C , Vrtovec Bojan , Hunt Sharon A , Haddad FranÇois
Published: April 2024

Background:
Hemodynamic parameters are routinely measured at 1 year after heart transplant but their prognostic implications have not been extensively studied. Previous research has suggested that post-transplant right ventricular diastolic dysfunction (RVDD) is a strong predictor of cardiac mortalities. However, these results have not been independently validated. Thus, we aim to evaluate the incidence, correlates, and prognostic implication of post-transplant RVDD defined as elevated ventricular operant diastolic elastance (Ed).

Methods:
All patients who underwent heart transplantation at Stanford University between 1999 and 2011 with right-heart catheterization at 1-year post-transplant were included. RV Ed was calculated as mean right atrial pressure divided by stroke volume (SV). Left ventricular (LV) Ed was calculated as mean pulmonary capillary wedge pressure divided by SV. Predefined RV Ed greater than 120 mmHg/mL and LV Ed greater than 200 mmHg/mL were considered significantly elevated.

Results:
In total, 216 patients were included in the study with mean age of 49±15 years. Abnormal RV Ed and LV Ed were found in 23% and 27% of the patients, respectively. RV Ed and LV Ed were strongly correlated with an r= 0.89 (P<0.001). Logistic regression analysis revealed that pre-transplant ventilatory support, cyclosporine-based therapy, LVEF <55% at 1 year, and cardiac allograft vasculopathy (CAV) at 1 year were strongly associated with RVDD (OR 11 (95% CI 1.6-76), 2.5 (1.2-5.6), 4.4 (2.0-9.9), and 9.6 (1.7-56) respectively). Patients with RVDD were at significantly increased risk of death with adjusted HR of 3.28 (95% CI 1.8-5.8). Other significant independent correlates include pre-transplant life support and history of rejections at 1 year.

Conclusion:
Post-transplant RVDD at 1 year is a strong independent predictor of outcome following heart transplantation. Further studies are warranted to see whether therapies targeted for RVDD could improve outcome.
Abstract 18340: Practice Patterns and Trends in the Use of Medical Therapy in Patients Undergoing Percutaneous Coronary Intervention
Authors: Garg Pallav , Yun Lingsong , Wijeysundera Harindra C , Cantor Warren , Ko Dennis T
Published: April 2024

Background:
Clinical guidelines emphasize medical therapy as the initial approach to the management of patients with stable coronary artery disease (CAD). It is unknown to what degree medical therapy is applied before Percutaneous Coronary Intervention (PCI) in practice. We evaluated the practice patterns in the use of medical therapy in stable CAD patients undergoing PCI, and whether the COURAGE study changed medication practice patterns.

Methods:
We evaluated medication prescription rates in 23,680 patients over 65 years of age with stable CAD undergoing PCI in Ontario between December 2003 and March 2010. Medication use before and after PCI was compared, including after stratification on comorbidities and Canadian Cardiovascular Society (CCS) angina class, and in the periods before and after the publication of the COURAGE trial (March 2007). Optimal medical therapy (OMT) was defined as prescription for beta-blocker, statin and either ACE-inhibitor or ARB in the 90 days prior to PCI and the same medications along with a thienopyridine in the 90 days following PCI and suboptimal as having been prescribed at least one of the above medications.

Results:
Compared to before PCI, more patients were on optimal medical therapy after PCI [11,149 (47.1%) vs. 8023 (33.9%), p<0.001]. Patients who were receiving OMT were more likely to have comorbidities, cardiovascular disease and had a prior stress test. Patients with angina at higher CCS class were less likely to be on OMT prior to PCI as compared with post-PCI (29.5% vs. 51.1%, p<0.001). 11,984 (50.6%) patients underwent PCI in the period before publication of the COURAGE trial. Before PCI, OMT rate was lower in the period after the COURAGE trial compared with before the trial (32.8% vs. 34.9%, p<0.001). The rate of OMT following PCI was lower in the period after the COURAGE trial compared with before the trial (47.3% vs. 46.9%, p<0.001).

Conclusion:
Among patients with stable CAD undergoing PCI, only a third of patients were prescribed OMT in the 90 days prior to their procedure, and less than half were receiving optimal medical therapy in the 90 days following PCI. There was no substantial change in medical therapy practice pattern over the study period, including following the publication of the COURAGE trial.
Abstract 18362: Proteomic and Metabolomic Profiling After Ischemia-Reperfusion Injury Reveals Bottlenecks That Underlie Cardioprotection in Hibernating Mammals
Authors: Quinones Quintin J , Ma Qing , Henao Ricardo , Lucas Joseph , Riess Matthias L , Bain James , Newgard Christopher B , Barnes Brian M , Podgoreanu Mihai V
Published: April 2024

Introduction:
Mammalian hibernation is a natural molecular adaptation to extreme environmental conditions with important applications for perioperative organ protection. We have previously shown in a surgical model of deep hypothermic circulatory arrest (DHCA) robust cardioprotection in hibernating arctic ground squirrels (AGS) compared with Brown Norway rats (Figure). We conducted an integrated proteomic and metabolomic analysis to identify species and season-specific correlates of the cardioprotective phenotype.

Methods:
Quantitative 5-fraction 2D-LC/LC-MS/MS was used to identify proteins expressed in the myocardium of summer active AGS, winter hibernating AGS, and rats subjected to DHCA followed by 3h or 24h of reperfusion, or sham (n=3-5/group). The complete sets of 5250 peptides for AGS and 8482 peptides for Rat were matched using an ENSEMBL referenced orthology map. Peptides from the same matched protein and species were log-transformed and summarized into protein level profiles by means of principal component analysis. Myocardial levels of 167 metabolites were quantified by MS.

Results:
Differentially expressed metabolic enzymes or transporters are paired with substrate and product in Table and reported as a ratio of change over baseline by species and hibernation status. Compared to AGS, rats developed metabolic TCA cycle substrate flux bottlenecks at the level of succinate dehydrogenase and malate transporter.

Conclusions:
Integration of observed changes in protein abundance with metabolic modules identified specific druggable targets for metabolic optimization that underlie the hibernator cardioprotective phenotype.
Abstract 18369: Interleukin-1 Blockade Improves Exercise Capacity in Heart Failure With Preserved Ejection Fraction (HFpEF): Results of the D-HART Study
Authors: Van Tassell Benjamin W , Arena Ross A , Oddi Claudia , Canada Justin , Abouzaki Nayef , Jahangiri Arehzo , Melchior Ryan , Falcao Raquel A , Kontos Michael C , Shah Keyur , Voelkel Norbert F , Dinarello Charles A , Abbate Antonio
Published: April 2024

Treatment options remain limited for patients with heart failure and preserved ejection fraction (HFpEF). Reduced exercise capacity is a common finding in HFpEF. Peak oxygen consumption (peak VO2) represents a gold standard for functional capacity and is a strong independent predictor of adverse outcomes. HFpEF patients also exhibit high levels of systemic inflammation that may be associated with mechanisms of diastolic dysfunction. We enrolled 12 patients with symptomatic HFpEF (LVEF>50% and evidence of abnormal LV relaxation, filling, diastolic distensibility, or diastolic stiffness) and elevated hsCRP (>2 mg/L). Patients were randomized to 14 day crossover treatment with daily subcutaneous injections of IL-1 receptor antagonist (anakinra); 100 mg or matching placebo in a double blind fashion (
NCT01542502
). The pre-specified primary endpoint was change in peak VO2. Cardiopulmonary exercise testing was performed at baseline and upon completion of each treatment course. We observed a significant improvement in peak VO2 (+1.1 vs -0.1 ml•kg-1•min-1, P=0.009) and the oxygen uptake efficiency slope (+0.23 vs +0.09, P=0.006) and a significant reduction in hsCRP (-84% vs -10%, P=0.006) upon completion of anakinra treatment versus placebo. Correlative studies also revealed significant associations between changes in peak VO2 and hsCRP (R=-0.60, P=0.002). Improvements in ventilator efficiency (VE/VCO2 slope) were limited to patients with above median values for ventilator efficiency (VE/VCO2 slope>26), suggesting that maximum benefits may occur in patients with impaired baseline function. These findings support the hypothesis that systemic inflammation and exercise intolerance in HFpEF are, at least in part, IL-1-dependent and provide the rationale for larger randomized clinical trials to confirm the benefits of IL-1 blockade in patients with HFpEF.
Abstract 18371: Regression of LV Mass After Transcatheter or Surgical Aortic Valve Replacement for Aortic Stenosis in the PARTNER I Trial
Authors: Stewart William , Lindman Brian R , Pibarot Philippe , Weissman Neil J , Hahn Rebecca T , McAndrew Thomas C , Goldstein Steven A , Rubenson David S , Leon Martin B , Kodali Susheel , Mack Michael , Svensson Lars , Thourani Vinod H , Herrmann Howard C , Douglas Pamela S
Published: April 2024

Background:
Regression of left ventricular hypertrophy (LVH) after aortic valve replacement (AVR) for aortic stenosis is a favorable response to ventricular unloading, but has not been compared in transcatheter (TAVR) vs. surgical AVR (SAVR) vs. medical management (MM).

Methods:
The PARTNER I trial randomized high risk patients to SAVR vs. TAVR (Cohort A), and inoperable patients to MM vs. TAVR (Cohort B). Patients with echocardiograms at all time points (baseline, 30, 180, and 365 days) after TAVR (A+B; n=197), SAVR (n=96), or MM (n=33) were stratified by gender-specific tertiles of baseline LV mass index (LVMi, g/m
2
) and change in LVMi over time was evaluated. We used ASE criteria (LVMi ≥122 g/m
2
for women, ≥149 g/m
2
for men) to define severe LVH.

Results:
Compared to baseline, at 1 year LVMi decreased from 151±40 to 130±33 g/m
2
in TAVR (p<0.001), 155±48 to 131±39 g/m
2
in SAVR (p<0.001), but not in MM (146±40 to 139±33 g/m
2
, p=ns). After TAVR and SAVR, regression of LVMi was significant in the middle and highest tertiles of LVMi (all p<0.005), with
similar regression in TAVR as SAVR
, mostly occurring by 180 days (Figure). At baseline, 56% of men and 70% of women in the AVR groups had severe LVH; compared to 33% of men and 39% of women at 1 year. MM patients showed a trend toward regression in the highest tertile (p=0.07), but not in the middle or lowest tertile. In the lowest tertile of LVMi, no change in LVMi occurred in either AVR group. Change in LVMi (baseline to 1 year) correlated to change in transvalvular mean gradient (baseline to 30 days) in TAVR (r=0.18, p=0.01), but not in SAVR or MM; there was no correlation with change in valve area in any group.

Conclusions:
LV mass regression was similar after TAVR or SAVR when baseline LVH was more marked (middle and highest tertiles), although one-third had residual severe LVH at 1 year. LV mass regression shows the end-organ correlates of hemodynamic improvement after both TAVR and SAVR, and requires further study.
Abstract 18377: Hypoplastic Left Heart Syndrome Derived Cardiac Stem Cells Show a Strong Regenerative Ability
Authors: Mishra Rachana , Sharma Sudhish , Chen Ling , Desmukh Savitha , Kaushal Sunjay
Published: April 2024

Background:
Human adult c-kit+ cardiac stem cells (CSCs) alleviates post-myocardial infarction left ventricle dysfunction in animal models and a Phase I clinical study. The regenerative capacity of CSCs in the very young patients with non-ischemic congenital heart defects has not been explored, even in the most surgically challenging Hypoplastic Left Heart Syndrome (HLHS) patients. We hypothesized that isolated HLHS neonatal-derived CSCs may have higher regenerative abilities than adult-derived CSCs and might address the anatomical deficiency of HLHS myocardium.

Methods and Results:
Human specimens were obtained during routine cardiac surgical procedures from right atrial appendage tissue discarded from 2 age groups: neonates and adults patients. We developed a reproducible isolation method that generated c-kit+ cells using immune-activated magnetic bead selection, regardless of the initial weight or age. Both groups had similar expression profile for c-kit+ (>85%), Ki67, TnT, GATA4+, and were negative for tryptase, collagen, and CD45. Both groups had similar proliferation doubling times. The neonatal-derived c-kit+ cells secreted higher levels of VEGF-A, ANG, and SDF-1α when compared to adult-derived c-kit+ cells. When transplanted into infarcted myocardium, neonatal-derived c-kit+ cells had a significantly higher ability to preserve myocardial function, prevent adverse remodeling, and enhance blood vessel preservation when compared to adult-derived c-kit+ CSCs.

Conclusions:
HLHS neonatal-derived c-kit+ cells have a strong regenerative ability when compared with adult-derived c-kit+ cells that may depend on angiogenic cytokines. This has important implications in the potential use of CSCs in future HLHS clinical trials.
Abstract 18378: Apical and Anterior Lead Location of Surgically Implanted Epicardial Left Ventricular Leads in Cardiac Resynchronization Therapy is Associated With Lower Survival Rate
Authors: CHEN Lu , Fu Haixia , Cha Yong-Mei , Birgersdotter-Green Ulrika M , Pretorius Victor
Published: April 2024

Introduction:
Surgically implanted epicardial left ventricular (eLV) lead is an alternative approach when transvenous LV (tLV) lead implantation in CRT patients has failed. With advancement in surgical technique and free from limitations of cardiac venous anatomy, operators have the freedom to choose the most optimal LV pacing site. Recent literatures noted differential clinical response in tLV-CRT patients with different LV lead locations. However, to the best of the authors’ knowledge, no such analysis has been published for eLV-CRT patients.

Hypothesis:
We hypothesize that optimal LV lead location in eLV-CRT is similar to tLV-CRT and similar clinical response is expected.

Methods:
After unsuccessful attempt(s) of tLV-CRT implantation, 44 (Age 63±15, 28M) patients received eLV-CRT from UCSD and Mayo Clinics between 2002 and 2013. Two-view (PA, lateral) chest radiographs were used to determine lead location by blinded independent observers. 9 patients were partially excluded from lead location analysis due to congenital cardiac anomaly or unavailable lateral chest radiograph. eLV lead locations were classified as basal, mid, or apical on the PA view; and anterior, anterolateral, lateral, posterolateral, or posterior on the lateral view. Survival data were collected from the national death and location database.

Results:
During an average follow up of 65 months, 15 patients have died following eLV-CRT implant. No death was attributed to acute surgical complication to eLV-CRT implantation. Kaplan-Meyer survival estimate showed anterior and apical eLV lead positions had lower survival rate as compared to non-anterior (p<0.01, figure A) and non-apical location (p=0.07, figure B).

Conclusion:
In this two-center study, apical and anterior eLV lead locations were associated with significantly lower survival rate. The study implies apical and/or anterior locations should be avoided, if possible, during eLV-CRT implantation.
Abstract 18388: Novel Study of the Dynamic Changes in Mitral Valve Annular and Leaflet Parameters Under Varying Loading Conditions: A Three-Dimensional Echocardiographic Study
Authors: AlHabdan Mohammed S , Colen Timothy , Klas Berthold , Tham Edythe , Hornberger Lisa , Smallhorn Jeffrey , Khoo Nee Scze
Published: April 2024

Background:
The impact of changing loading conditions on mitral valve (MV) coaptation is controversial. Previous studies assessed the MV at mid or end-systole only, hence MV dynamic changes throughout systole are poorly understood. We used three-dimensional echocardiography (3DE) to explore dynamic changes in MV annular and leaflet parameters during loading stress and inotropy in an animal model.

Methods:
In open chest model, 8 pigs and 4 dogs were imaged epicardially. 3DE was performed at baseline, with dobutamine infusion, volume infusion and aortic constriction, with a return to baseline hemodynamics between each intervention. The 3DE datasets were analyzed offline using TomTec semi automated MV software. Leaflet (AL) and annular area (AA) were reported as % change from baseline in 5 systolic intervals (1-5; each representing 20% of systole). ANOVA was performed between each intervention and baseline, at the 5 intervals, with Dunnett’s correction.

Results:
At baseline, MV peak % change of AL and AA occurred during the 4th and 5th intervals respectively. Compared to baseline, dobutamine infusion % change AL was reduced (-5.9% ± 3.8 vs -9.4% ± 6.1, p<0.01) in the 3rd interval, whilst % change AA was reduced throughout systole. With volume loading, % change AL and AA were significantly reduced during intervals 2 to 5. In contrast, with aortic constriction % change AL (-5.9% ± 3.8 vs -2.4% ± 4.8, p<0.05) and %change AA (-1.6% ± 3.8 vs 1.5% ± 5.7, p<0.05) were increased at the 3rd interval (see Figure).

Conclusion:
Peak MV annular contraction and leaflet apposition occurs in late systole. MV leaflet coaptation area improves in response to increased contractility and pre-load by increasing annular contraction and reducing unopposed leaflet surface. In contrast, increased afterload has the opposite effect on annular and leaflet size, potentially worsening coaptation. The timing of peak annular contraction and leaflet apposition has implications for the design of future MV studies.
Abstract 18428: Implication of HDAC1/HDAC2 in Paracrine Protection of Mesenchymal Stem Cells Following Acute Myocardial Ischemia
Authors: Wang Meijing , Wang Lina , Turrentine Mark
Published: April 2024

INTRODUCTION:
We have previously indicated that inhibition of histone deacetylase1 (HDAC1) or HDAC2 promoted cardiomyogenic potential of mesenchymal stem cells (MSCs). But little is known regarding implication of HDAC1 or HDAC2 in MSC-induced paracrine protection. We and others have shown that MSCs mediate their beneficial effects primarily via paracrine action. In this study, therefore, we
hypothesize
that MSCs with specific inhibition of HDAC1 or HDAC2 not only possess increased cardiomyogenesis, but are able to acutely improve cardiac function following ischemia/reperfusion (I/R).

METHODS:
MSCs were isolated from bone marrow (femur/tibia) of C57BL mice, and transfected with siRNAs of scramble, HDAC1, or HDAC2. Conditioned medium (CM) was collected from these transfected MSCs. Cardiac I/R was performed in isolated mouse hearts via Langendorff. 1.5ml CM was infused immediately before ischemia. Heart tissue was studied for activation of STAT3 and caspase3. Data were analyzed with two-way ANOVA, p<0.05=statistically significant.

RESULTS:
Decreased HDAC1 or HDAC2 expression was observed in HDAC1 or HDAC2 siRNA transfected MSCs (Figure A). Inhibition of HDAC1 or HDAC2 resulted in increased expression of cardiac α-MHC
,
troponin I, and troponin T. Infusion of CM from MSC transfected with HDAC1 siRNA or HDAC2 siRNA significantly improved myocardial function following acute I/R as did CM from the cells treated with scramble siRNA (Figure B). Increased activation of myocardial STAT3 (a pro-survival signaling) was noticed among CM-pretreated groups after I/R compared to media control, whereas active caspase3 was reduced in these groups (Figure C).

Conclusion:
Our results represented initial evidence, showing that specific inhibition of HDAC1 or HDAC2 not only increased cardiomyogenesis of MSCs, but retained their paracrine protection following acute I/R. This study provides new understanding for modification of MSCs to optimize their therapeutic efficacy.
Abstract 18429: Transmembrane Protein 88: A Wnt Regulatory Protein That Specifies Cardiomyocyte Development
Authors: Palpant Nathan , Pabon Lil , Rabinowitz Jeremy , Hadland Brandon , Stoick-Cooper Cristi , Paige Sharon , Bernstein Irwin , Moon Randall , Murry Charles
Published: April 2024

Genetic regulation of the cell fate transition from lateral plate mesoderm to the specification of cardiomyocytes requires suppression of Wnt/β-catenin signaling, but the mechanism for this is not well understood. By analyzing gene expression and chromatin dynamics during directed differentiation of human embryonic stem cells (hESCs), we identified a suppressor of Wnt/β-catenin signaling, transmembrane protein 88 (TMEM88), as a potential regulator of cardiovascular progenitor cell (CVP) specification. During the transition from mesoderm to the CVP, TMEM88 has a chromatin signature of genes that mediate cell fate decisions, and its expression is highly up-regulated in advance of key cardiac transcription factors in vitro and in vivo. In early zebrafish embryos tmem88a is expressed broadly in the lateral plate mesoderm including the bilateral heart fields, and morpholino-mediated reduction in its expression yields small hearts with defective looping. Short hairpin RNA targeting of TMEM88 during hESC cardiac differentiation increases Wnt/β-catenin signaling, confirming its role as a suppressor of this pathway. TMEM88 knockdown has no effect on Nkx2.5 or GATA4 expression, but 80% of genes most highly induced during CVP development have reduced expression, suggesting adoption of a new cell fate. In support of this, analysis of later stage cell differentiation showed that TMEM88 knockdown inhibits cardiomyocyte differentiation and promotes endothelial differentiation. Taken together, TMEM88 is critical for heart development and acts downstream of GATA factors in the pre-cardiac mesoderm to specify lineage commitment of cardiomyocyte development through inhibition of Wnt/ß-catenin signaling.
Abstract 18437: Distinct Roles of Akt Isoforms in the Development of Hypoxia Induced Pulmonary Hypertension
Authors: Tang Haiyang , Chen Jiwang , Drennan Abigail , Fraidenburg Dustin , Zimnicka Adriana , Smith Kimberly A. , Garcia Joe G.N. , Machado Roberto F. , Makino Ayako , Yuan Jason X.-J.
Published: April 2024

Rationale:
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by persistent increase in pulmonary arterial pressure associated with vascular remodeling due to excessive pulmonary vascular cell proliferation and migration. Akt/mTOR signaling is involved in regulating cell growth, proliferation, migration and apoptosis. Akt is comprised of three isoforms, Akt1, Akt2, and Akt3, with distinct but overlapping functions. The aim of this study is to examine whether the Akt/mTOR pathway is activated in pulmonary arterial smooth muscle cells (PASMC) from patients with PAH and animals with experimental pulmonary hypertension (PH), and to examine whether Akt1 or Akt2 deficient mice are protected against hypoxia-mediated PH (HPH).

Methods:
Lung tissues from control subjects and PAH patients as well as control mice and mice with (HPH) were used to study changes in Akt/mTOR mRNA and protein levels using real-time PCR and Western blotting, respectively. WT, Akt1-/- and Akt2-/- mice were exposed to 10% oxygen for up to five weeks. Pulmonary vascular remodeling was evaluated using tissue morphometrics. Right ventricle systolic pressures (RVSP) and right ventricular hypertrophy by RV/(LV+S) ratios were measured to evaluate pulmonary hypertensive changes. Acute hypoxia-induced pulmonary vasoconstriction response, in both WT and KO mice, was evaluated by isolated perfused / ventilated mouse lung.

Results:
Phosphorylation of Akt and mTOR in lung tissues from PAH patients was significantly increased in comparison to the controls. Akt/mTOR signaling was upregulated in rat and mouse lungs with hypoxia-induced pulmonary hypertension. Akt1-/- mice had significantly lower RVSP, RV/LV+S ratios, and displayed less pulmonary vascular remodeling when compared to WT mice. AKT1-/- mice also had significantly lower pulmonary arterial pressure in response to acute pulmonary vasoconstriction challenges than their WT counterparts.

Conclusion:
These data indicate that Akt/mTOR signaling plays an important role in the development and progression of pulmonary vascular remodeling in patients and animals with PH. This study suggests a key role for Akt1 in vascular remodeling processes and provides a novel therapeutic target for treatment of PAH.
Abstract 18457: Outpatient Milrinone Therapy as a Bridge to Pediatric Heart Transplantation: A Large Single Center Experience
Authors: Auerbach Scott R , Cavanaugh Jean , Pietra Biagio , Miyamoto Shelley D
Published: April 2024

Objective:
Milrinone infusion as treatment of end stage heart failure in children is well established. Previous reports of outpatient milrinone therapy (tx) are limited by small numbers. Our objective was to evaluate the safety of outpatient milrinone tx as a bridge to heart transplant (HT).

Methods:
We retrospectively reviewed the records of all patients (pt) at our institution that have received outpatient milrinone tx between February 2000 and June 2013.

Results:
A total of 53 pt received outpatient milrinone tx, all had failed milrinone weaning, all began milrinone as an inpatient, and all had an indication of bridge to HT. The median age was 9.7 years [IQR 2-16] and 27 (51%) were male. The diagnosis prior to HT was congenital heart disease (15), cardiomyopathy (21; 16 dilated and 5 restrictive), and graft failure (17). Successful HT was performed in 52 and 1 pt is alive waiting. The median length of stay (LOS) for initiation of milrinone was 7 days (d) [IQR 2-16]. There were 2737 d of outpatient milrinone tx without a death and the median duration of tx was 28 d [IQR 15-62; range1-377]. The mean dose was 0.5 ± 0.02 mcg/kg/min. Arrhythmias occurred in 2 pt (atrial flutter and 3 beats of non-sustained ventricular tachycardia). There were 27 rehospitalizations in 16 pt for a total 97 inpatient days with a median LOS of 2d [IQR 1-3]. Indications for rehospitalization were atrial flutter (1pt, 3d),worsening heart failure (4pt, 26d, median LOS=3d [IQR 1-11]), central venous line (CVL) malfunction (10 pt, 23d, median LOS = 1d [IQR 1-2], CVL infection (2 pt, 5d, mean LOS = 2.5d +/- 0.71, and other (16pt,10 admissions, 40d, median LOS=2d [IQR 1-6]. One pt with worsening heart failure was admitted for additional inotropic support with dopamine and remained an inpatient until HT.

Conclusion:
There was no mortality in patients on milrinone awaiting HT. Arrhythmias were rare and catheter related complications were infrequent. The outpatient use of milrinone in children is safe and effective when initiated in the inpatient setting and it may reduce costs and improve quality of life in children awaiting HT.
Abstract 18478: Depletion of Prolyl-4-Hydroxylase Domain 3 Protects Hearts From Injury Induced by Ischemia/Reperfusion and Inhibits Cardiomyocyte Apoptosis
Authors: Xie Liang , Wang Zhongjing , Aitsebaomo Julius , Pi Xinchun , Willis Monte S , Patterson Winston
Published: April 2024

PHD3, a member of a family of Prolyl-4 Hydroxylase Domain (PHD) proteins, has long been considered as a pro-apoptotic protein. Although the pro-apoptotic effect of PHD3 requires its prolyl hydroxylase activity, it is independent of HIF-αs, the common substrates of PHDs. PHD3 is highly expressed in the heart, however, its role in cardiomyocyte apoptosis remains unclear. Whether depletion of PHD3 is cardioprotective need to be determined. To determine whether inhibition or depletion of PHD3 inhibits cardiomyocyte apoptosis and attenuates myocardial injury induced by ischemia-reperfusion, PHD3 knockout mice and their littermate control mice were subjected to left anterior descending (LAD) coronary artery ligation for 40 minutes and then released for reperfusion. By performing Evan’s Blue, triphenyl-tetrazolium chloride and TUNEL staining, we demonstrated that myocardial injury and cardiomyocyte apoptosis were significantly attenuated in PHD3 knockout mice. There were no changes of HIF-1α protein level, the expression of HIF target genes or myocardium capillary density in PHD3 null mice. In vitro, DNA damage response (DDR) and cardiomyocyte apoptosis induced by oxidative stress were significantly inhibited by prolyl hydroxylase inhibitor or depletion of PHD3. Interestingly, DDR activated by hypoxia-reoxygenation (H/R) was also inhibited by inhibition of PHD3. Therefore, we conclude that depletion or inhibition of PHD3 protected hearts from injury induced by ischemia-reperfusion and inhibited cardiomyocyte apoptosis induced by oxidative stress or hypoxia-reperfusion. DDR induced by oxidative stress was dramatically inhibited by depletion or inhibition of PHD3, which may partly contribute to the cardioprotective effect of depletion of PHD3.
Abstract 18489: Predictors of Successful Chemical Cardioversion With Dofetilide in Patients With Persistent Atrial Fibrillation
Authors: Reddy Madhu Y , Janga Pramod , Pamulapati Hema , Bakhtiani Ramchandur , Reddy Namratha , Vallakati Ajay , Atkins Donita , Bommana Sudharani , Howard Patricia , Berenbom Loren , Lakkireddy Dhanunjaya
Published: April 2024

Introduction:
Dofetilide induced cardioversion in persistent atrial fibrillation (AF) patients is not well described. We intended to evaluate the incidence and predictors of chemical cardioversion after initiation of Dofetilide in patients with persistent AF.

Methods:
We performed a retrospective study including all patients with persistent AF who were admitted for initiation of Dofetilide in our center. Patients in sinus rhythm (SR) at the time of initiation were excluded. All patients were in the hospital for a minimum of 5 doses of the drug. If patients did not convert to SR spontaneously on the drug by the 4
th
dose, they underwent electrical cardioversion (DCCV).

Results:
Of the 305 patients who underwent dofetilide initiation at our center, 195 (64%) persistent AF patients were in AF at the time of the first dose. Mean age of the population was 65 ±9 years with 61 (31%) females. Mean CHADS2 score was 1.7 ±1.0. Median duration of AF was 36 (IQ 12-84) months with a mean LA diameter of 4.6±0.8cm. Mean number of prior failed antiarrhythmic drugs (AAD) was 1.4 ±1.1. Spontaneous conversion to SR occurred in 91 (47%) patients. Patients who converted to SR were much more likely to be females (40% vs 24%; p = 0.020) and had smaller left atrial diameter (4.4 vs 4.7cm; p = 0.023). In multivariate analysis including age, gender, duration of AF, number of prior AADs, LA diameter, heart failure and LVED, the only independent predictor of successful chemical cardioversion was female gender (OR: 2.4; p = 0.022).

Conclusion:
In patients with persistent AF, female gender is independently associated with successful chemical cardioversion with dofetilide.
Abstract 18501: A Major Opportunity for Obstetricians and Gynecologists: Improving Awareness of Cardiovascular Disease Among Women
Authors: Brusati Allison J , Rosser Mary L
Published: April 2024

Background:
Cardiovascular disease (CVD) is the number one killer of women in the US, yet many women are still unaware of their risk of heart disease. A large ethnic gap in awareness exists: black and Hispanic women correctly identified CVD as their greatest health threat 36% and 34% of the time, respectively, compared to 56% of American women overall (Mosca 2013). We sought to determine the proportion of women who name heart disease as the leading killer of women in a diverse urban hospital in New York City. We also sought to determine which providers women see for primary care and if heart health was discussed by Ob/Gyns.

Methods:
A 33-question survey was administered to women (age 18 and older) at 5 Ob/Gyn clinics affiliated with a large urban academic hospital center.

Results:
1013 questionnaires were completed. Of the female population analyzed, 63.3% were 18-40 years old and 35.3% were 41+ years old. Respondents were 40% Hispanic, 31% black, 20% white, 9% multi-ethnic and 30.5% have high school or less education and 42% have annual household income less $30K. Of all women sampled, only 28% were able to cite heart disease as the number one killer of women, 55% of these respondents were white and 21% were non-white (p<0.01). Young women identified CVD less frequently than older women (21% v 40%) (p<0.01). Respondents reported seeing an Ob/Gyn for annual visits more frequently than an Internist (66% v 48%) (p<0.01). This response was consistent among all age and ethnic groups analyzed. Most women (65%) (p<0.01) perceive that their Ob/Gyn does not discuss their heart health. This finding is consistent among non-white women (64%) and women 18-40 years old (66%).

Conclusions:
Young, non-white women are least aware of cardiovascular disease as the leading killer of women. Awareness (21%) among non-white women in this urban, ethnically diverse part of New York City is even lower than levels of awareness reported among minorities nationally. These very women are more likely to see an Ob/Gyn annually than any other physician, and yet few women report that Ob/Gyns discuss their heart health. Given the high morbidity of CVD in women, Ob/Gyns should take advantage of their enormous access to young, reproductive aged women to begin a dialogue about heart health aimed at prevention.
Abstract 18510: Pericardiectomy Impact on Cardiac Index in Patients With Constrictive Pericarditis
Authors: Alraies M Chadi , Yingchonch?aroen Teerapat , Senapati Alpana , Tariq Mohammad U , Klein Allan L
Published: April 2024

Background:
Advanced constrictive pericarditis (CP) has been associated with change in cardiac hemodynamics including cardiac output and cardiac index (CI). Etiology and duration of constriction can affect recovery of CI postpericardiectomy. We sought to look into the change in post-operative cardiac index (CI) among different CP etiologies using echocardiogram and right heart catheterization.

Methods:
We Included 301 patients from Cleveland Clinic pericardial disease database with surgically confirmed CP form 1999 to 2010. Post-operative CI was measured using Fick method immediately before and after pericardiectomy. The bootstrap-validated analysis of covariates was performed to compare the mean of post-operative CI among different CP etiologies after adjustment with baseline relevant covariates.

Results:
Etiology of CP was idiopathic in 136 patients (45%), viral in 24 patients (8%), prior cardiac surgery in 89 patients (30%), autoimmune in 30 patients (10%) and radiation treatment in 22 patients (7%). Mean CI was reduced and improved after pericardiectomy (2.1±0.7 L/min/m2 to 3.0±0.8 L/min/m2, p<0.001). After adjustment for age, gender, NYHA, LVEF, RVSP, medial e’, lateral e’ and pre-operative CI, the post-operative CI recovered based on different etiologies (2.99±0.7, 3.07±0.16, 3.00±0.09, 3.48±0.15 and 2.76±0.17 L/min/m2 for Idiopathic, viral, prior cardiac surgery, autoimmune and post radiation respectively, p=0.019) (Figure1).

Conclusion:
Post-operative cardiac index recovery is related to underlying etiology. Considering CP etiology for patient selection for pericardiectomy may identify patients who will benefit from the surgery and avoid post-pericardiectomy low cardiac output syndrome that may lead to early post-operative mortality
Abstract 18526: Catheter Ablation as a First-Line Therapy for Atrial Fibrillation - A Meta-Analysis
Authors: Vallakati Ajay , Reddy Madhu Y , Ponnaganti Gopi C , Yarlagadda Vivek , Atkins Donita , Bommana Sudharani , Janga Pramod , Mahankali Sridhar Arun Raghav , Maybrook Ryan , Pimentel Rhea C , DiBiase Luigi , Natale Andrea , Dawn Buddhadeb , Lakkireddy Dhanunjaya
Published: April 2024

Introduction:
Catheter ablation (CA) has been shown to be superior to anti-arrhythmic therapy (AAD) for drug-refractory atrial fibrillation (AF). Whether CA is superior to AAD as a first-line therapy for AF is not clear. We performed meta-analysis of all prospective studies assessing the efficacy of CA as first line therapy for paroxysmal AF.

Methods:
We searched PubMed, Cochrane library and Embase for observational studies and randomized control trials (RCT) assessing CA as first-line therapy for AF. Recurrence rates of AF after CA and AADs in these studies were extracted and analyzed. Random effects model with inverse variance weighting was used to calculate relative risk (RR) of AF recurrence after CA in comparison to AADs.

Results:
We identified 5 prospective trials (3 RCTs and 2 observational) (n=597) of which 3 RCTs compared the efficacy of CA with AADs and the other 2 observational studies evaluated AF recurrence after CA (no comparator group). Follow-up duration ranged from 12 to 24 months across the studies. In these 5 studies, 353 and 244 AF patients received CA and AADs as first line therapy respectively. Pooled data of 353 CA patients revealed AF recurrence rate of 0.28 (95% CI, 0.23 - 0.33). Pooled data of 244 patients who received AADs revealed AF recurrence of 0.44 (95% CI, 0.38 -0.51). Random effects model including the 3 RCTs demonstrated that catheter ablation was associated with a significantly lower AF recurrence rate when compared with AADs (RR: 0.5; 95% CI, 0.28 -0.89; p =0.02).

Conclusion:
As a first-line therapy strategy for paroxysmal AF, CA is associated with 50% lesser recurrence of AF when compared to AADs.
Abstract 18529: Protease-Activated Receptor-1 Deficiency Reduces Doxorubicin-Induced Cardiotoxicity
Authors: Antoniak Silvio , Mackman Nigel
Published: April 2024

Objective:
The administration of doxorubicin (Dox), a potent effective anti-cancer anthracycline drug, is limited by its cardiotoxicity and coagulation activation. This study was conducted to investigate whether there is a direct connection between the increased thrombin-mediated signaling via the protease-activated receptor 1 (PAR-1) and the cardiotoxicity after Dox administration.

Methods and Results:
PAR-1-/- mice and wild-type (WT) littermates were subjected to a single injection of Dox (20mg/kg) or a weekly injection of Dox (5mg/kg) for 5 weeks. Changes in heart size, heart function and cardiotoxicity were measured by echocardiography 5 days or 5 weeks after injection (p.i.). Direct effects of thrombin during Dox stimulation was analyzed on neonatal cardiomyocytes and fibroblasts in vitro. PAR-1-/- mice were protected from Dox-induced cardiac injury and had preserved left ventricular function 5 days p.i. compared to WT littermates (fractional shortening: 53.7±1.8% vs. 43.9±2.0%; P<0.05). The hearts of PAR-1-/- mice had less cardiac expression of 3-Nitrotyrosine, KC and MPO compared to WT mice 5 days p.i.. Furthermore, the hearts of Dox-treated PAR-1-/- mice exhibited increased activation of pro-survival AKT and less acetylation of pro-apoptotic p53 compared to treated WT mice. In addition, PAR-1-/- mice had improved heart function compared WT mice at the 5 weeks’ time point (Dox cumulative dose 25mg/kg). In vitro experiments confirmed the deleterious effects of a thrombin-mediated PAR-1 activation during Dox incubation. Rat cardiomyocytes exhibited increased release of cardiac troponin I which was associated with increased levels of p53 acetylation. Furthermore, Dox-induced p53 accumulation in mouse fibroblast was enhanced by thrombin.

Conclusion:
These results indicate that PAR-1 activation contributes to Dox-induced cardiotoxicity by enhancing inflammatory response and apoptosis. These findings suggest that PAR-1 antagonist may be useful in preventing Dox-induced heart failure in cancer patients.
Abstract 18532: New Prognostic Factors in Heart Failure With Preserved Ejection Fraction: The KaRen Study
Authors: Erwan Donal , LUND Lars H , oger emmanuel , Hage camilla , daubert jean-claude , linde cecilia
Published: April 2024

KaRen was a prospective multicentre study identifying predictors of outcome in patients with Heart Failure and preserved Ejection Fraction (HFpEF).

Method:
539 patients were included following an acute HF presentation accompanied with BNP> 100 pg/mL or NT-proBNP>300 pg/mL and LVEF > 45%. 438 patients were reassessed after 4 -8 weeks clinically, biologically and by ECG and echocardiography. ECG (18 variables) and echo (117 variables) were analysed in core centres. Patients were followed for vital status and hospitalisation every 6 months during a minimum of 18 months. The primary endpoint was time to all-cause death or first HF hospitalisation. A Cox proportional hazard modelling was applied. The multivariable model included univariable covariates at and below the significance level p=0.15 added by age and gender.

Patients:
The mean age was 76± 9 years and 57% were women. A history of HF was found in 40.4 %. Patients′ history included hypertension in 78.5%, atrial tachyarrhythmia in 58%, anemia in 47.2%, diabetes in 31.3%, renal dysfunction in 37.9%. At the acute event, LVEF was 56±7 %. Of the patients 6.1 % had first degree AV block and 14.9% had QRS width > 120 ms. Right bundle branch block (BBB) was present in 6.6% and Left BBB in 3.7%.

Results:
During a mean follow-up time of 21.6 months a primary outcome event occurred in 204 patients (46.5%)
,
consisting of 101 deaths (23%) and 142 HF-hospitalizations (32.5%). Candidate predictors of outcome are: First degree AV block was the only dyssynchrony criteria independently predicting outcome (p=0.04); tricuspid regurgitation (mean±standard deviation = 2.87±0.64 m/s, p=0.0009) and mean e’ velocity > 5.5cm/s (mean±standard deviation = 7.95±2.58, p=0.0009) were the two echocardiographic predictors. Ongoing ACE (ARB) treatment was the only positive predictor of outcome.

CONCLUSION:
The KaRen study recruited a representative population of HFpEF patients with a high rate of clinical events (23% deaths).First degree atrio-ventricular block and increased pulmonary arterial pressures and left ventricular diastolic dysfunction were independently associated with outcome. These novel data may provide new information improving the management of HFpEF patients.