bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 19049: Net Clinical Benefit of Vorapaxar in NSTE ACS: Role of Ischemic and Bleeding Risk Stratification
Authors: Tricoci Pierluigi , Huang Zhen , Van de Werf Frans , White Harvey , Moliterno David , Lewis Basil , Held Claes , Bode Christoph , Ogawa Hisao , Lokhnygina Yuliya , Aylward Philip , Wallentin Lars , Harrington Robert , Mahaffey Kenneth , Armstrong Paul
Published: April 2024

Background:
In 12,944 NSTE ACS pts included in the TRACER trial, platelet protease-activated-receptor 1 (PAR-1) antagonist vorapaxar, on top of standard of care with high thienopyridine use, was associated with an 11% reduction in CV death, MI, or stroke and an increased risk of bleeding. The trial was broadly inclusive and did not exclude pts based on bleeding risk. We evaluated the net clinical benefit of vorapaxar in the randomized population and according to patients’ predicted risks of ischemic events and major bleeding.

Methods:
Using multivariable models developed in the TRACER placebo group to predict 1-yr major bleeding (GUSTO severe or TIMI major bleeding) and recurrent ischemic events (composite of CV death, MI, stroke), patients were stratified into 2 bleeding risk categories (predicted rate >5% vs ≤5%) and 2 ischemic risk categories (predicted rate >13% vs ≤13%). Net clinical outcome was measured as the difference in treatment effects on the composite ischemic endpoint vs bleeding outcome.

Results:
Overall at 1-yr, vorapaxar resulted in a 1.30% absolute reduction in CV death, MI, and stroke and a 0.94% absolute increase in GUSTO severe bleeding (net benefit +0.34%). In pts with an increased risk of bleeding, vorapaxar had negative net clinical benefit (Figure). Among pts with high risk of ischemic events but low risk of bleeding (26% of the population), vorapaxar produced a favorable 2.8% absolute net benefit.

Conclusion:
Vorapaxar was associated with an improved net benefit in a selected but large group of NSTE ACS patients with high risk of recurrent ischemic events and low risk of bleeding, identified through the application of multivariable risk stratification strategies. Appropriate selection of patients in NSTE ACS, with the risk of bleeding balanced against that of recurrent ischemic events, appears to be a determinant of improved outcome with vorapaxar added to standard of care and high use of dual antiplatelet therapy.
Abstract 19074: NPPA Overexpression in Mice Increases Susceptibility to Atrial Fibrillation
Authors: Galimberti Eleonora S , Kannankeril Prince , Kor Kaylen , Muhammad Raafia , Blair Marcia , Darbar Dawood
Published: April 2024

Introduction:
Mutations in natriuretic peptide precursor A (NPPA) gene, which encodes atrial natriuretic peptide (ANP), have been linked with familial atrial fibrillation (AF). Although the precise mechanism by which NPPA mutations cause AF remains unclear, a shortening of the atrial action potential was demonstrated in an isolated rat heart model. Here, we overexpressed NPPA in a mouse model testing the hypothesis that these mice would be more susceptible to AF.

Methods:
A triple FLAG-tag (FLAG) was fused in-frame with the 3’ end of the either the wild-type (WT) human NPPA (WT-NPPA-FLAG) cDNA or the mutant NPPA peptide containing the COOH-terminal 12 amino acid extension (mut-NPPA-FLAG) isolated from individuals with familial AF. The FLAG-tag does not diminish NPPA biological activity. The expression of the mutated protein was confirmed by measuring mRNA by polymerase-chain reaction (PCR). We used transesophageal atrial pacing (15 second bursts from 50 to 15 ms) to assess inducibility and duration of AF.

Results:
Serial weekly transesophageal pacing starting at 16 weeks of age was performed in WT-NPPA-FLAG and mut-NPPA-FLAG mice. Mut-NPPA-FLAG mice had inducible AF at 16 weeks of age in 61±0.1% compared to WT-NPPA-FLAG (n=6 mice, P<0.05). In addition, induced AF was longer lasting in the mut-NPPA-FLAG as compared to WT (AF burden: 19.2±2.9 [mut] sec vs. 12±4.1 s [WT], P<0.05).

Conclusions:
We show that humanized NPPA overexpression mice are more susceptible to AF with longer AF episodes compared with WT using esophageal pacing.
Abstract 19087: Improved Survival After Percutaneous Stenting of the Atrial Septum in Human Fetal Left Atrial Hypertension
Authors: Chaturvedi Rajiv , Ryan Greg , Seed Michael , Jaeggi Edgar
Published: April 2024

Hypoplastic left heart syndrome with a highly restrictive or intact atrial septum (HLHS-RAS) has a very high mortality. The associated fetal LA hypertension results in abnormal lung development with lymphangiectasia and pulmonary vein muscularization. We report our experience of ultrasound-guided stenting of the human fetal atrial septum.

Methods and Results.
Retrospective review of fetuses with HLHS-RAS or a variant that underwent active perinatal management from 2000-January 2012. Ten fetuses were identified. Two fetuses became hydropic and died in utero (33, 29 weeks). Four fetuses required the urgent creation of an atrial communication immediately after birth but subsequently died (5-54 days), secondary to pulmonary hypertension. More recently, the atrial septum was stented in four fetuses at 28-36 weeks without maternal general anesthesia. Elevated left atrial pressure, massive dilatation of the pulmonary veins and MRI estimated pulmonary perfusion all improved after stenting. Two fetuses developed stent stenosis with recurrence of LA hypertension in utero for approximately four weeks and 1 day respectively. Three of four stented fetuses were born by vaginal delivery. Atrial septectomy and additional procedures were performed within 72 hours of birth. Intraoperative lung biopsy demonstrated muscularized pulmonary veins and lymphangiectasia in all four. Two died at 17 and 53 days of age from pulmonary hypertension and sepsis, respectively. The other two are still alive, a significant improvement in survival (p=0.03).

Conclusion.
Fetal left atrial decompression by stenting may improve survival in HLHS-RAS.
Abstract 19121: Prediction of Sudden Cardiac Death in Patients with Mild to Moderate Chronic Heart Failure: A Comparative Study of Early Repolarization and Fragmented QRS
Authors: Ozu Kentaro , Yamada Takahisa , Morita Takashi , Furukawa Yoshio , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Naito Takashi , Fujimoto Tadao , Kondo Takumi , Sengoku Kaoruko , Yamomoto Hironori , Kawai Tsutomu , Takahashi Satoshi , Fukunami Masatake
Published: April 2024

Background:
Identification of patients with chronic heart failure (CHF) at risk for sudden cardiac death (SCD) is an important objective. Early repolarization pattern (ERP) and fragmented QRS (fQRS) on the standard 12-lead ECG have recently been associated with an increased risk of life-threatening ventricular arrhythmias in patients with chronic coronary artery disease. However, there is little information available on the comparison of the prognostic significance for SCD between ERP and fQRS in patients with CHF.

Methods:
We studied 132 consecutive outpatients (NYHA class: 2.0±0.6), with radionuclide left ventricular ejection fraction less than 40% (30±7%), who were enrolled in our prospective cohort study. All patients underwent the standard 12-lead ECG at enrollment. We assessed the presence of ERP, using the criteria of J-point elevation ≥0.1 mV in at least 2 inferior or lateral leads. fQRS was defined by the presence of >2 notches on the R wave or the S wave and had to be present in >or=2 contiguous inferior (II, III, aVF), lateral (I, aVL, V(6)) or anterior (V(1) to V(5)) leads. The primary endpoint of this study was SCD.

Results:
At enrollment, 16 and 30 patients had ERP and fQRS, respectively. During the mean follow-up period of 6.7±3.5 yrs, 26 patients had SCD. Kaplan-Meier analysis showed that SCD was observed significantly more frequently in patients with than without ERP (63% vs 14%, p<0.0001), and also in patients with than without fQRS in ≥ 2 territories (anterior and inferior, anterolateral or inferolateral), (45% vs 17%, p=0.044). A multivariate Cox analysis revealed that ERP was significantly and independently associated with SCD (hazard ratio 3.7 (95%CI 1.6-8.6), p=0.002), although fQRS in ≥2 territories showed a significant association with SCD (p=0.034) at univariate analysis .

Conclusion:
ERP in inferior leads would be more strongly associated with an increased risk of SCD in patients with mild to moderate CHF, in comparison to fragmented QRS.
Abstract 19130: Referral to Cardiac Rehabilitation: A Quality Indicator Associated with Reduced Mortality
Authors: Martin Billie-Jean , Hauer Trina , Austford Leslie D , Southern Danielle A , Knudtson Merill L , Arena Ross , Aggarwal Sandeep , Stone James A
Published: April 2024

Background:
Cardiac Rehabilitation (CR) is an efficacious, evidence based treatment for reducing mortality and hospitalization in subjects with coronary artery disease (CAD). CR referral is an indicator of quality care in CAD patients. However, not all eligible subjects are referred for CR. The objective of this study was to assess predictors of referral to CR and the association between referral and mortality.

Methods:
All subjects who underwent coronary angiography between 1995 and 2009 and were found to have CAD were included in this study (n=25,958, 24.6% female). Referral to CR and subsequent attendance were evaluated. Baseline characteristics were compared between those who were referred and not. Logistic regression models predicting referral were developed. Using cox proportional hazards models, survival was then compared across those who were not referred (NR), referred and did not attend, and referred and did attend.

Results:
Of those subjects with CAD, 10236 (39.4%) were referred to CR; 58.4% of those referred attended CR. Rates of referral increased from 20.7 to 65.3% over the course of the study (p<0.0001). In multivariate models, older age, being female, and diabetes all predicted non-referral (all p<0.0001). Relative to the NR, those who were referred and did not attend had a hazard ratio (HR) for mortality of 0.55 (95% CI 0.51, 0.60); those who were referred and attended had a HR of 0.26 (95% CI 0.24, 0.29). When adjusted for age, sex, CAD severity, treatment (surgical, interventional, medical) and all clinical covariates, subjects who were referred and did not attend had a HR of 0.76 (95% CI 0.70, 0.82) and subjects who were referred and attended had a HR of 0.42 (95% CI 0.38, 0.46) for death relative to those who were NR.

Conclusion:
While CR referral rates have improved over time, they remain suboptimal. High-risk subjects are the most likely to remain un-referred. Given the association between CR referral and reduced mortality, referral to CR is a justifiable quality indicator for CAD patient care. Efforts to improve referral should be undertaken.
Abstract 19153: Brachial Artery Diastolic Diameter is Associated with Noncalcified Coronary Artery Plaque Volume
Authors: Vaidya Dhananjay , Kral Brian G , Yanek Lisa R , Moy Taryn F , Becker Diane M , Becker Lewis C
Published: April 2024

Background:
Studies suggest that atherosclerosis in a primary vascular bed may be accompanied by generalized systemic remodeling in nonatherosclerotic vessels, resulting in larger arterial diameters, and that remodeling is related to plaque composition and stage of disease. We thus examined the extent to which diastolic brachial artery diameter (BAD) is associated with the extent of calcified (CP) and noncalcified coronary artery plaque (NCP) in an asymptomatic population of persons with a family history of early coronary artery disease.

Methods:
In 405 subjects (58% women, 37% African-American, mean age 51.2 ± 10.6 years), we measured BAD using B-mode ultrasound. Coronary plaque was assessed using 256 multidetector dual-source coronary CT angiography and total volumes of CP and NCP were calculated using a validated automated quantitation method. The association of resting BAD with NCP and CP plaque volumes was tested using two separate linear mixed models adjusted for age, sex, race, current smoking, diabetes, hypertension, body mass index, total and HDL-cholesterol, and nonindependence among family members.

Results:
NCP was present in 43.2% (N= 175) and CP in 37.5% (N= 152). The median BAD [IQR] was 4.6 [3.9 to 5.3] mm for persons with any plaque (n= 179) compared to 4.1 [3.6 to 4.6] mm for those without plaque (p < 0.001). The unadjusted Spearman rho of BAD with NCP was 0.38 (p < 0.001) and with CP was 0.32 (p < 0.001). Among persons with plaque, there was a significant independent association between BAD and the extent of NCP (beta 38%/1mm larger BAD, p < 0.001), but not with the extent of CP (beta 1%/1mm larger BAD, p=0.95).

Conclusions:
This study demonstrates a strong relationship between BAD, as a marker of systemic arterial remodeling in non-atherosclerotic vessels, and an incremental amount of noncalcified coronary plaque but not calcified plaque. This suggests that expansive vascular remodeling may occur with larger amounts of soft noncalcified plaque as an early adaptive response, whereas calcified plaque may represent a later atherogenic stage with a decrease in BAD adaptive potential. Studies are needed to examine plaque composition and its relation to systemic arterial remodeling in order to address prevention implications.
Abstract 19168: Effect of Endurance Exercise on Transgenic Arrhythomeginc Right Ventricular Cardiomyopathy Mice
Authors: Jain Rahul , Martherus Ruben , Takagi Ken , James Jeanne , Kramer Kristen , Purevjav Enkhsaikhan , Towbin Jeffrey A
Published: April 2024

Introduction:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disorder that causes sudden death and right ventricular heart failure in the young. Clinically, it has been suggested that competitive sports may accelerate ARVC pathogenesis in susceptible persons. The goal of this study was to investigate the cause and effect of exercise stress in the development of ARVC using a transgenic (Tg) mouse model with cardiac-restricted overexpression of human mutant R2834H desmoplakin (DSP).

Methods:
DSP
R2834H
Tg (Tg-mut), non-transgenic human wild type DSP
WT
(Tg-wt) and control non-transgenic (Ntg) mice were divided into groups, sedentary and exercise. Mice in the exercise group were subjected to graded increase in intensity of exercise on a treadmill from the age of 4 weeks. Every 4 weeks, echocardiograms (echo) and ECGs (single lead) were recorded. Mice were dissected for tissue sampling and gross morphology.

Results:
Initial echo data results are as shown in Table 1. When adjusted for age, number of days exercised, gender, interaction of genotype and exercise status, Tg-mut RV was bigger than Ntg mice (P=0.0005). Within the Tg-mut group, the RV diameter was not statistically significantly different between exercise and sedentary mice when adjusted for same variables. Heart weight/body weight ratio was higher in Tg-mut as compared to Ntg & lcub;sedentary (= 0.001) and exercise group (P = 0.0060} and Tg-wt. Tissue staining showed early development of fibrosis and fat in Tg-mut mice. The only significant ECG finding occurred in the exercise group: Tg-muthadincreased P wave amplitude and decreased R wave amplitude (P = 0.02 and P =0.001, respectively) compared to Ntg mice.

Conclusions:
We report significant early histopathologic, and ECG changes with exercise in mutant DSP
R2834H
Tg mice compared to Ntg and Tg-wt mice.
Abstract 19187: Sublingual Glycocalyx Measurement, a Novel Non-Invasive Technique to Predict Coronary Artery Disease
Authors: Brands Judith , Vink Hans , Pacella John J
Published: April 2024

Background:
A relatively thick endothelial lining, known as the glycocalyx (GC), forms the true interface between flowing blood and the vascular wall. The GC regulates several key endothelial functions including vascular permeability, coagulation and inflammation and contributes to the protection against atherogenic challenges. In healthy blood vessels, the GC provides limited access to flowing red blood cells (RBC). Recent observations have suggested that RBCs penetrate deeper into a damaged GC and therefore may serve as a marker for GC damage, which has been associated with microcirculatory dysfunction that accompanies, among others, coronary artery disease (CAD). Aim: In the present study we tested whether the presence of CAD could be predicted by measuring the dimension of the RBC perfused boundary region (PBR), which fills up the space between median RBC column width (MCW) and the outer edge of RBC permeable vascular lumen. In healthy blood vessels PBR is relatively small due to limited penetration of RBC into the GC and it is hypothesized that PBR will increase for a given MCW when GC is damaged.

Method:
We used sidestream dark field imaging, a novel stroboscopic LED ring-based clinical imaging modality, of the sublingual microvasculature in subjects with (N=10) and without (N=10, controls) angiographic CAD. From these images, MCW and PBR were determined in over 3000 vascular segments (vessel diameter between 10 and 20µm) per subject.

Results:
CAD patients displayed a significant increase in PBR compared to controls. The mean PBR increased from 2.31 ± 0.09µm to 2.64 ± 0.11µm (P<0.05) comparing controls with CAD patients, respectively, consistent with a 0.3 µm deeper penetration of RBCs into the GC.

Conclusion:
These data demonstrate that CAD patients have a significant increase in the width of the RBC accessible component of the sublingual microvascular GC compared to control subjects. A wider permeable portion of the GC indicates a change in GC structure which may be associated with a reduced vascular protective function of the GC. Moreover, SDF imaging might provide a novel, noninvasive method to detect CAD.
Abstract 19213: Establishment of Mechanically-Assisted Primary Bidirectional Cavopulmonary Shunt in Neonates and Infants: An Acute Human Pilot Study
Authors: Honjo Osami , Merklinger Sandra , Poe John , Guerguerian Anne-Marie , Taylor Katherine , Zhang Hargen , Van Arsdell Glen
Published: April 2024

Background:
One year survival for stage 1 palliation in hypoplastic left heart syndrome (HLHS) is 69%. We hypothesized that primary ‘in-series’ palliation (neonatal bidirectional cavopulmonary shunt - BCPS) with mechanical assist would provide more stable physiology. This is the first human study of an acute intraoperative BCPS model.

Methods:
Two types of intraoperative, tubing configured, pump-assisted BCPS circulations [superior vena cava (SVC) to pulmonary artery (PA) pump assist at stage I Norwood, and SVC to right atrium (RA) pump with oxygenation at stage II BCPS] were established in the operating room for 20 minutes at the time of modified ultrafiltration (Figure 1A). Hemodynamics and cerebral blood flow were continuously recorded. Arterial and venous blood gases were analyzed every 5-10 minutes.

Results:
All six patients (3 in each group) completed 20 minutes of mechanical support without hemodynamic compromise. In the SVC-PA pump assist (n=3), the pump generated effective pulmonary blood flow of 335+/-53ml/min while the BT shunt was occluded. Compared to Norwood physiology, the SVC-PA pump-assisted BCPS had a higher mean arterial pressure (median 33 vs. 44 mmHg, p=0.02), lower central venous pressure (CVP) (12 vs. 10 mmHg, p=0.03), and higher cerebral perfusion pressure (33 vs. 46 mmHg, p=0.01) (Figure 1B). In the SVC-RA oxygenation assist (pump and oxygenator assisted BCPS), the pump generated blood flow of 536+/176ml/min with oxygenation. Compared to baseline BCPS physiology, SVC-RA oxygenation-assisted BCPS had a lower CVP (14 vs. 7 mmHg, p=0.05).

Conclusion:
The study demonstrates the physiologic feasibility of mechanically assisted neonatal in-series single ventricle circulation. Both assist systems attained equivalent or better hemodynamics, stable ventilation and oxygenation, and a more favorable cerebral perfusion profile. This human proof of concept study raises the possibility of a potential paradigm shift for the treatment of HLHS.
Abstract 19236: Mapping the Role of the Mitochondrial Phosphate Carrier in Cardiomyocyte Life and Death
Authors: Gutierrez-Aguilar Manuel , Baines Christopher P
Published: April 2024

Under pathologic conditions, mitochondria from cardiomyocytes experience a change in the highly selective transport of ions and metabolites to a non-selective permeability state. The Mitochondrial Permeability Transition Pore (MPTP) is a voltage-sensitive unselective channel thought to initiate such changes resulting in necrotic cell death during heart disease. While the biochemical behavior of the MPTP has been characterized
in extenso
, its molecular identity has remained an open question. Previous evidence suggesting Voltage Dependent Anion Channels and Adenine Nucleotide Translocators as putative components of this pore has been casted in doubt as genetic models lacking such proteins still exhibit an MPTP. So far, the mitochondrial Cyclophilin D (CypD) is the only widely accepted MPTP regulator. CypD is known to bind to proteins in the mitochondria such as the F
0
F
1
-ATP synthase lateral stalk and the Mitochondrial Phosphate Carrier (PiC) among others. Here we demonstrate that an N-terminal segment of CypD binds the C-terminus of the PiC by using pulldown assays and molecular docking simulations. In addition, we have generated three different transgenic mouse lines overexpressing the PiC at a medium and high level and a double transgenic line co-expressing PiC and CypD. Our results show that cardiac-specific PiC overexpression at the high level results in an MPTP with lesser sensitivity to Ca
2+
, possibly due the ability of Pi to buffer matrix Ca
2+
. These results suggest CypD binds to the PiC thus contributing to MPTP regulation.
Abstract 19248: Atrial Fibrillation/Flutter Associated with Rheumatoid Arthritis vs. Osteoarthritis and the use of Etoricoxib vs. Diclofenac: Results from the MEDAL Program
Authors: Kohli Payal , Laine Loren , Kaur Amarjot , Curtis Sean , Cannon Christopher P
Published: April 2024

Background:
The use of non-steroidal anti-inflammatory drugs (NSAIDs) and rheumatoid arthritis (RA) have been associated with atrial fibrillation/flutter (AF) and adverse cardiovascular outcomes in registry studies. The MEDAL program provides a unique opportunity within the context of large randomized controlled trials to explore this relationship.

Methods:
MEDAL represents a pooled population from 3 trials; 34,701 patients with osteoarthritis (OA) or RA randomized to receive either a coxib (etoricoxib, 60 or 90 mg daily) or a non-selective NSAID (diclofenac 150 mg daily) had a mean follow up of 18 months. All patients who received at least one dose of study drug were included in the analyses (modified Intent to Treat). AF events occurring on study drug, defined as serious or resulting in drug discontinuation (reported up to 14 days after last date of drug), were counted and unadjusted incidence rates are reported in this post-hoc analysis.

Results:
Overall, the rates of AF in the study were low (0.5%). More patients with AF were male, ≥65 years, white race, and had ≥2 coronary risk factors (p<0.01 for all). Patients with OA had a slightly higher mean age than those with RA (64.0 vs. 61.2 years) and a somewhat higher proportion of coronary risk factors. In the pooled treatment group (selective plus non-selective NSAIDs), there was a slightly
lower
rate of AF in patients with RA compared with OA (0.4% vs. 0.6%). When stratified by treatment group and type of arthritis, the highest rate of AF occurred in patients receiving etoricoxib 90 mg and having OA (0.7%) (Figure).

Conclusion:
Within the MEDAL program, patients with RA did not appear to have a higher unadjusted rate of AF than patients with OA. Furthermore, 90 mg etoricoxib in patients with OA was associated with a higher rate of AF relative to a non-selective NSAID and this relationship may be dose-related. These data suggest greater degrees of COX-2 inhibition may increase the risk of AF, although the absolute risk is small.
Abstract 19355: Tissue Doppler Imaging For Rejection Surveillance in Pediatric Heart Transplant Recipients
Authors: Lunze Fatima I , Gauvreau Kimberlee , Colan Steven D , Blume Elizabeth D , Smith Rex Neal , Perez-Atayde Antonio , Singh Tajinder P
Published: April 2024

Conventional echocardiography is not considered reliable for rejection-surveillance in pediatric heart transplant (HT) recipients. Pulse-wave tissue Doppler imaging (TDI) is geometry-independent and more sensitive than conventional imaging to evaluate bi-ventricular function. The purpose of this study was to assess TDI findings during biopsy-proven rejection in pediatric HT recipients and to develop TDI criteria for absence of rejection with high predictive accuracy.

Methods:
All HT recipients in follow-up at our center were included (N=122, median age at transplant 8.7 yrs, range 2 weeks-22 yrs). We identified all echocardiograms with TDI imaging performed within 24 hrs of an endomyocardial biopsy during 2005-2011. Rejection was defined as ISHLT Grade ≥2R cellular rejection or antibody-mediated rejection. Paired comparisons of TDI velocities were made using each patient’s baseline TDI as control.

Results:
Overall, 650 biopsy-pairs were identified where there was no rejection by biopsy at baseline (median duration between paired biopsies 4.3 mo, 25th-75th percentile 1-8.7 mo). In 25 of these pairs, the second biopsy demonstrated cellular or antibody mediated rejection. Rejection was associated with 27±17 % decline in LV S’ (P<0.001), 17±25 % decline in RV S’ (P<0.001) and a 16±18 % decline in septal S’ velocity (P<0.001). Using a receiver-operating characteristic curve, <24% decline in LV S’, <15% decline in RV S’ and <12% decline in septal S’ were all individually associated with a negative predictive value (NPV) of 98% for rejection. When all three criteria were met, the NPV was 98.5% (95% CI 96.9%, 99.4%) for rejection. Overall, 83% of biopsy pairs met criteria of 98.5% NPV for rejection.

Conclusions:
Biopsy-proven rejection in pediatric HT recipients is associated with significant and easily measured changes in ventricular function using TDI echocardiography. Using well-defined TDI criteria to predict absence of rejection, over 80% of planned biopsies may be deferred or avoided at minimal risk to pediatric HT recipients.
Abstract 19413: Regulation of I
Ks
Current Amplitude by Differential Trafficking Patterns and Interactions Of KCNQ1 and KCNE Subunits
Authors: Wang Yuhong , Jiang Min , Zhang Mei , Henderson Scott , Tseng Gea-Ny
Published: April 2024

KCNQ1 (Q1, pore-forming subunit) and KCNE1 (E1, modulatory subunit) associate to form the slow delayed rectifier (I
Ks
) channel that functions as ‘repolarization reserve’ in human heart. We have shown that in adult guinea pig (GP) cardiomyocytes Q1 & E1 cluster to different subcellular compartments, and the degree of Q1/E1 colocalization affects the I
Ks
amplitude. We have also shown that KCNE2 (E2) is expressed in human heart, and can associate with Q1 or Q1/E1 to suppress the I
Ks
amplitude.

Objectives:
To study the patterns of trafficking and interactions of Q1, E1 and E2.

Methods:
Q1, E1 and E2 are labeled with eGFP (Q1-G) or mono-dsR (Ex-R, x = 1 or 2) and expressed in COS-7 cells, neonatal rat (NRVM) and adult GP (AGPV) ventricular myocytes; the latter 2 by adenoviral (Adv) gene transfer. Protein trafficking/interactions are monitored by live cell imaging, in conjunction with patch clamping, immunocytochemistry & immunoblotting.

Results:
Time courses of Q1-G & Ex-R distribution in COS-7 cells suggest that they are translated, packaged and shipped to the cell surface independent of each other. They meet on the cell surface and form Q1-G/Ex-R complexes. Q1-G/Ex-R complexes are endocytosed and colocalized in a cytosolic tubulo-vesicular system. We identify 2 main effects of Ex-R on Q1-G trafficking: (1) Ex-R accelerates Q1-G recovery after photobleaching, (2) 24-48 hr after transfection, E2-R brings Q1-G with it to lysosomes for increased degradation. The distribution patterns of Q1-G and Ex-R in NRVM are similar to those in COS-7 cells. However, under the same Adv incubation conditions, Q1-G and Ex-R are expressed at a much lower level in AGPV than NRVM. In AGPV, Q1-G is distributed mainly as cytosolic striations while Ex-R mainly on cell surface, similar to the native Q1 and Ex immunofluorescence patterns seen in control myocytes.

Conclusions:
Assembly of Q1 & E1 into I
Ks
does not occur early during biogenesis. Q1 & E1 meet after they reach the plasma membrane and travel together thereafter. E1 increases the mobility of Q1, while E2 increases Q1 degradation in lysosomes. In adult cardiomyocytes the expression levels and subcellular distribution patterns of Q1 & Ex are tightly regulated, with the sarcomere structure playing a key role in Q1 localization.
Abstract 19425: Stress Perfusion Cardiac Magnetic Resonance Predicts Risk of Cardiac Events in Patients with Established Coronary Artery Disease
Authors: Shah Ravi , Heydari Bobak , Coelho-Filho Otavio , Francis Sanjeev , Murthy Venkatesh , Pencina Michael , Abbasi Siddique , Feng Henry , Neilan Tomas , Blankstein Ron , Steigner Michael , Jerosch-Herold Michael , Kwong Raymond
Published: April 2024

BACKGROUND:
Current prognostic risk assessment has limited sensitivity for identification of patients at high risk for cardiac events with established CAD. We evaluated the prognostic value of stress cardiac magnetic resonance (CMR) imaging to reclassify risk in patients with established CAD.

METHODS:
We performed clinically indicated stress CMR imaging in 815 patients, with follow-up for cardiac death (CD) or acute myocardial infarction (AMI; primary outcome) over a median 1.9 years. Univariate and multivariate Cox regression models were used to determine clinical and imaging characteristics associated with risk. Annual event rates were calculated and stratified by presence and absence of prior CAD. Net reclassification improvement and ROC analysis were used for the addition of inducible ischemia by CMR beyond a best-overall clinical multivariate model of risk for discrimination and reclassification.

RESULTS:
Of the 815 patients referred for stress CMR, 13 failed to complete CMR (2%), and 97% had interpretable image quality. Inducible ischemia (ISCH) strongly independently predicted primary outcome in CAD patients (HR = 8.17, 95% CI 2.9-23.1, p = 0.0001). No ISCH was associated significantly improved event-free survival in patients with and without CAD (p<0.001) and a <1% annual rate of CD, with lower annual rates of CD/AMI in patients with and without CAD. ISCH improved risk discrimination over a best-overall clinical risk model (p<0.0001). Addition of ISCH to the best-overall clinical model resulted in a net reclassification improvement of 0.229 (95% 0.063-0.391, p<0.05).

CONCLUSIONS:
Inducible ischemia by stress CMR is a powerful, independent prognostic marker in patients with symptomatic, established CAD. A negative stress CMR is associated with a <1% rate of CD, and reclassifies risk of future cardiac events in patients otherwise considered at moderate or high risk by clinical assessment.
Abstract 19450: Manual Thrombus Aspiration is not Associated with Reduction in Infarct Size Assessed by Delayed Enhancement MDCT
Authors: Sim Doo Sun , Kim Yun-Hyeon , Lee Daun , Seon Hyun Ju , Jeong Myung Ho , Cho Jeong Gwan , Park Jong Chun , Ahn Youngkeun
Published: April 2024

Objective:
We sought to assess whether manual thrombus aspiration could reduce infarct size in patients with acute ST-elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention (PCI).

Background:
The efficacy of manual thrombus aspiration during primary PCI for acute MI remains controversial.

Methods:
Between April 2009 and Mar 2011, 86 consecutive patients presenting with first acute STEMI (Killip≤II) within 12 hours after the symptom onset were randomized to manual thrombus aspiration (group I, N=44) or conventional PCI without thrombus aspiration (group II, N=42). The use of glycoprotein IIb/IIIa inhibitor (GPI) was left to the discretion of the operator. All patients received aspirin 300 mg and clopidogrel 600 mg before PCI and underwent delayed enhancement (DE) multi-detector computed tomography (MDCT) immediately after PCI without injection of an additional contrast media for assessment of infarct size, determined as the total volume of myocardium showing DE. DE MDCT was repeated at 2 months after PCI. The primary endpoint was infarct size reduction at 2 months.

Results:
Baseline clinical characteristics and angiographic findings were similar between the 2 groups. There were no differences between group I and II in symptom-to-door time, door-to-balloon time, PCI-to-MDCT time, Pre-PCI TIMI 0/1, post-PCI TIMI 3, or the use of GPI. Markers of myocardial reperfusion showed better outcome in group I but without statistical difference: ST-resolution rate >70% (74% vs. 65%), myocardial blush grade 3 (88% vs. 68%), and corrected TIMI frame count <28 (31% vs. 24%). Initial infarct size determined by DE MDCT and left ventricular ejection fraction (LVEF) by 2-dimensional echocardiography were similar between group I and II (17±18 mL vs. 22±23 mL and 58±11% vs. 55±10%, respectively). At 2 months, there was no difference in infarct size and left ventricular ejection fraction between the groups: 14±10 mL vs. 17±12 mL and 62±12% vs. 60±2%, respectively. No adverse cardiac events occurred in either group during the 2-month clinical follow-up.

Conclusion:
Manual thrombus aspiration was not associated with reduction in infarct size in patients with acute ST-elevation MI undergoing primary percutaneous coronary intervention.
Abstract 19452: Prrx1 Interacts with and Inhibits Pitx2 Function
Authors: Dolmatova Elena , Cooper Rebecca R , Ellinor Patrick T
Published: April 2024

Background:
Genome-wide association studies have identified 9 genomic loci associated with atrial fibrillation (AF) two of which are located at chromosomes 4q25 and 1q24 near the genes PITX2 and PRRX1 respectively. Pitx2 is crucial for the heart development and its loss leads to the inducible AF in mice. Since Prrx1 is a transcriptional co-activator we hypothesized that it may interact with and modulate Pitx2 function.

Methods:
We assessed the expression pattern of Pitx2 and Prrx1 in mouse atria by qPCR. Using an in vitro overexpression system we tested if Prrx1 and Pitx2 are present in a complex via co-immunoprecipitation studies (co-IP). We then made serial deletion constructs to determine the site of Prrx1 interaction with Pitx2. We assessed functional consequences of this interaction by siRNA knock-down followed by qPCR and luciferase reporter assays on the Prrx1, ANF, and HCN4 promoters.

Results:
Pitx2 and Prrx1 had a similar expression pattern in adult mouse atria with a 3.4±0.85 fold overexpression for Pixt2 and 1.7±0.55 fold for Prrx1 in LA, compared to RA (p<0.05). Our co-IP data show that Prrx1 and Pitx2 are present in a complex with binding site located at the homeodomain of Pitx2 (aa72-92, aa119-139, and aa131-151 for Pitx2a, Pitx2b and Pitx2c respectively). SiRNA knockdown studies in atrial cell line showed that knockdown of Pitx2 reduced Prrx1 expression by 71±29% (p<0.05) and Pitx2 knockdown reduced Prrx1 expression by 56±21% (p<0.05). Prrx1 but not Pitx2 knockdown caused 68±29% and 65±28% reduction in HCN4 and ANF mRNA levels respectively. All Pitx2 isoforms activated Prrx1 promoter by 4.3±2.7 fold in luciferase reporter assay, and this effect was abolished by addition of Prrx1 (p<0.05). Similar results were seen with ANF promoter: Pitx2 increased promoter activity by 2.2±0.2 fold, and addition of Prrx1 brought it back to baseline (p<0.05). In contrast, neither Prrx1, nor Pitx2 had significant effect on HCN4 promoter activity.

Conclusions:
Our data show that in vitro Prrx1 and Pitx2 are present in a complex. Further, we demonstrate that Prrx1/Pitx2 interaction has functional consequences that alter expression of some atria-specific genes. Thus, the Prrx1/Pitx2 interaction may be an interesting regulatory mechanism in the susceptibility to the AF.
Abstract 19494: PGC-1α Mediates Anti-Remodeling Impact of cGMP-PDE5 Inhibitor in Failing Hearts
Authors: Zhu Guangshuo , Zhang Manling , Kaludercic Nina , Bedja Djahida , Lee Dong I , Sasaki Hideyuki , Kariya Taro , Paolocci Nazareno , Gabrielson Kathleen , Kass David , Takimoto Eiki
Published: April 2024

Background:
The transcriptional coactivator peroxisome proliferator-activated receptor- coactivator 1 (PGC-1α) is a master regulator of mitochondrial biology, regulating cardiac mitochondrial metabolism and oxidative stress, and its down-regulation has been implicated to play a key role in pathogenesis of heart failure. NO-cGMP signal reportedly up-regulates PGC-1α in adipose tissue. We hypothesize that cGMP signal activation by sildenafil (SIL) up-regulates PGC-1α in cardiac myocytes and ameliorates cardiac failure remodeling.

Methods and Results:
Neonatal rat ventricular myocytes (NRVM) exposed to phenylephrine (20µM 96hr) revealed ∼40% down-regulation of PGC1α and impaired mitochondrial respiration (65% decrease in respiratory control ratio, RCR), both of which were normalized by SIL (1µM). Direct cGMP-PKG activation by adenoviral PKG overexpression in NRVM up-regulated PGC1α, and increased mitochondrial respiration (120% with glutamate/malate substrate), whereas enhanced mitochondrial respiratory function was abrogated when PGC1α was silenced. These suggest cGMP-PKG up-regulates PGC1α and modulate mitochondrial respiration in cardiac myocytes. We next tested in vivo role of this regulation using animals lacking in PGC1α (KO). In wild type controls (WT), pressure-overload (TAC) induced dilating remodeling at 1-2 wk, which further develops failure over 7wks, associated with ∼50% down-regulation of PGC-1α, reduced mitochondrial biogenesis and respiratory function (RCR), and increased oxidative stress. SIL treatment (100mg/kg/day 6wk) up-regulates PGC1a, and improves all of these features, including RCR for all three substrates. In contrast, KO hearts developed significantly worse remodeling after 3wk of pressure-overload induction (%FS, WT-TAC: 41.08±7.50 vs. KO -TAC: 32.90 ± 12.08 at 3wk, WT-TAC: 34.30±7.51 vs. KO-TAC:19.90 ± 1.84 at 7wk). Importantly, 6wk Sil treatment did not have any impact on this late remodeling progression or mitochondrial respiratory function in KO hearts.

Conclusion:
Sildenafil reverses cardiac failure remodeling process via a PGC-1α dependent mechanism. This highlights the beneficial actions of sildenafil for the treatment of heart failure.
Abstract 19517: Pro-Angiogenic MicroRNA-27b Retards EPC Apoptosis and Accelerates Wound Healing in Type 2 Diabetes via Suppressing p53 and Bax/Bcl-2 Ratio
Authors: Wang Jie-Mei , Cai Jing-Jing , Yuan Hong , Chen Alex F
Published: April 2024

Introduction:
Endothelial progenitor cells (EPCs) are promising candidates for autologous cell therapy of diabetic wound repair because of their high angiogenic potentials. However, increased EPC apoptosis in diabetes directly limits its clinical success. MicroRNAs are endogenous non-coding RNAs that regulate gene expression at the post-transcriptional level, but their roles in EPC-mediated angiogenesis in diabetes are incompletely understood. We hypothesized that the pro-angiogenic miR-27b inhibits EPC apoptosis and improves wound healing in type 2 diabetes.

Methods and Results:
Bone marrow-derived EPCs from adult male type 2 diabetic db/db mice and their normal littermates db/+ mice were used. MiR-27b expression (real-time PCR) in EPCs was decreased by >66% in db/db vs. db/+ mice (n=4, p<0.05). The impaired EPC angiogenesis of >70% (Matrigel tube formation, n=4, vs. db/+) and increased EPC apoptosis (TUNEL staining, n=3, p<0.05 vs. db/+) in diabetes were rescued following miR-27b mimic transfection (n=3, p<0.05 vs. db/db + scramble). p53 and Bax/Bcl-2 ratio in EPCs (Western blot analyses) were significantly higher in db/db mice (by 23% and 58%, respectively, vs. db/+), which were suppressed by miR-27b mimic (n=3, p<0.05 vs. db/db + scramble). Excisional wound (6-mm diameter) closure was markedly delayed in db/db vs. db/+ mice (n=5, p<0.05), accompanied by poorer wound angiogenesis (Laser Doppler detection, n=5, p<0.05) and elevated expression of p53 (> 72%) and Bax/Bcl-2 ratio (> 55%) (both n=5 vs. db/+). Local delivery of miR-27b mimic or cell therapy using diabetic EPCs (10
6
) with miR-27b mimic transfection significantly accelerated wound closure rates (n=5, p<0.05), with a concomitant augmentation of wound perfusion in db/db mice (n=5, p<0.05).

Conclusion:
miR-27b retards EPC apoptosis and accelerates wound healing in type 2 diabetic mice, at least in part, via suppressing p53 and Bax/Bcl-2 ratio. These findings may provide a mechanistic basis for rescuing EPC dysfunction in diabetes for successful autologous cell therapy.
Abstract 19519: Patient Health Questionnaire-9 Correlates with Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire in Measuring Heart Failure Patient Well-Being and Predicting Outcomes
Authors: Tate Jesalyn A , Davis Mary E , Markus Tiffanie M , Lenihan Daniel J
Published: April 2024

Introduction:
The assessment of patient well-being and correlation with outcomes is especially difficult, particularly with HF patients. Currently, the time-consuming Kansas City Cardiomyopathy Questionnaire (KCCQ) and Minnesota Living with Heart Failure Questionnaire (MLHFQ) are typically used only in research protocols; conversely, the PHQ-9 is a much simpler questionnaire that can be completed and scored in a typical clinical setting.

Hypothesis:
We hypothesized that the scores of the PHQ-9 correlate with the scores of the KCCQ and MLHFQ, and that for clinical purposes, it may be beneficial to substitute the longer questionnaires with the PHQ-9.

Methods:
Using data obtained through the Vanderbilt Main Heart Registry, we compared patient scores on the KCCQ and MLHFQ in each depression category (none, mild, moderate, moderately-severe, and severe) in 294 patients with heart failure, as defined by patient PHQ-9 scores. We also assessed survival data for the patients that have been followed up to two years with annual PHQ-9 scores to evaluate the correlation between depression category and mortality.

Results:
The study group (N=294) was 55 years (range 18-90) and 60% male, most with symptomatic HF (93% ≥ NYHA II)( Table 1.). Twenty-five percent of patients with severe depression are deceased. Preliminary results indicate there is a direct correlation between PHQ-9 category and corresponding KCCQ (p < 0.001) and MLHFQ (p < 0.001) scores (Figure 1.).

Conclusion:
Our findings suggest that the PHQ-9 can be readily used as a screen for depression and quality of life in HF patient in the clinical setting. Additionally, PHQ-9 score appears highly correlated to major outcomes.
Abstract 19526: Fractional Flow Reserved Derived from Computed Tomographic Angiography (FFRCT) to Discriminate Individuals with versus without Ischemia: Results from the DeFACTO Trial (Determination of Fractional Flow Reserve by Anatomic Computed TOmographic Angiography)
Authors: Min James K , Berman Daniel , Shaw Leslee J , Mauri Laura , Koo Bon-Kwon , van Mieghem Carlos , Erglis Andrejs , Leipsic Jonathon
Published: April 2024

Background
Non-invasive fractional flow reserve (FFR) derived from coronary computed tomographic (CT) angiography (FFRCT) is a novel method that employs computational fluid dynamics to diagnose coronary lesions that cause ischemia. To date, the per-patient diagnostic performance of FFRCT versus obstructive CAD by CT (>50% stenosis) to discriminate ischemia has been inadequately studied.

Methods
A total of 407 vessels were evaluated in 252 patients from 17 centers in 4 countries who underwent CT, FFRCT, invasive coronary angiography and invasive FFR. The area under the receiver operator characteristics curve (AUC) for detecting abnormal FFR on a per-patient basis was examined considering: (1) all vessels interrogated by FFR (n=252 patients), (2) only vessels >2 mm interrogated by FFR (n=149 patients); 3) a decision rule which included all vessels interrogated by FFR, as well as vessels with maximal stenosis 90% which were considered negative and positive, respectively, for ischemia (n=252 patients); and 4) a decision rule for >2 mm vessels (n=229 patients). Per-patient AUCs were compared for FFRCT alone, CT stenosis >50% alone, and the combination of FFRCT and CT stenosis >50%. FFRCT was superior to CT stenosis for discrimination of individuals with ischemia (AUC 0.81 vs. 0.69, p2 mm vessels (AUC 0.82 vs. 0.74, p=0.0007), when employing the decision rule (0.83 vs. 0.67, p2 mm vessels (0.92 vs. 0.68, p<0.0001). The combination of FFRCT and CT stenosis was similarly superior to CT stenosis alone when considering all vessels interrogated by FFR (0.81 vs. 0.69, p2 mm vessels (0.82 vs. 0.74, p<0.001), when applying the decision rule (0.83 vs. 0.67, p2 mm vessels (AUC 0.91 vs. 0.68, p<0.0001). In contrast, no added discrimination was noted when CT stenosis was added to FFRCT, as compared to FFRCT alone (p=NS).

Conclusion
FFRCT improves discrimination for identification of individuals who manifest ischemia. The addition of CT stenosis findings to FFRCT does not improve discrimination of individuals with ischemia.
Abstract 19596: Endothelial Acyl-CoA Synthetase 1 is not Required for Saturated Fatty Acid- Mediated Inflammatory and Apoptotic Effects
Authors: Gonzalez Oscar , Li Xin , Barnhart Shelley , Kramer Farah , Shen Xia , Vivekanandan-Giri Anuradha , Kanter Jenny E , Handa Priya , Pennathur Subramaniam , Pennathur Subramaniam , Kim Francis , Coleman Rosalind A , Schaffer Jean E , Bornfeldt Karin E
Published: April 2024

Saturated fatty acids, such as palmitic (C16:0) and stearic acid (C18:0), cause detrimental effects in endothelial cells (ECs) that might contribute to macrophage accumulation in adipose tissue and the vascular wall in states of obesity and insulin resistance. Fatty acids require conversion into acyl-CoA derivatives to exert most biological effects, a reaction catalyzed by acyl-CoA synthetases (ACSL). We hypothesized that endothelial deficiency of ACSL1, an ACSL isoform mediating inflammatory effects in myeloid cells, would protect from detrimental effects of saturated fatty acids in vitro and saturated fat feeding in vivo. Mouse microvascular CD45-negative-CD31-positive endothelial cells (MMECs) were isolated from lungs or hearts by fluorescence activated cell sorting. In these cells and in bovine aortic ECs (BAECs), saturated fatty acids caused JNK activation, ER stress, and apoptosis, along with increased inflammatory activation, as measured by an increase in the release of the soluble adhesion molecules sICAM-1 (p<0.01), and sVCAM-1 (p<0.01), as well as release of the chemokine CCL2 (p<0.05). In order to evaluate the role of endogenous ACSL1 in ECs, a conditional endothelial Acsl1-deficient mouse model was generated. Acsl1-deficient MMECs had significantly decreased beta-oxidation as measured by decreased acid soluble metabolite production (WT 393.1 ± 25.6, KO 270.5 ± 16.3 cpm/µg protein; p<0.05). However, conditional endothelial ACSL1-deficiency did not protect against the inflammatory or apoptotic effects of saturated fatty acids in vitro, nor did it protect insulin resistant mice fed a saturated fatty acid-rich diet from epididymal adipose tissue accumulation of macrophages or increased aortic adhesion molecule expression. Conversely, forced Acsl1 overexpression in BAECs exacerbated the effects of saturated fatty acids on apoptosis and ER stress, in part through increased JNK activation. In conclusion, forced overexpression of Acsl1 can exacerbate some effects of saturated fatty acids; however, endogenous ACSL1 is not required for pro-inflammatory or pro-apoptotic responses of ECs to saturated fatty acids.