bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17706: A Common Variant in the PTPN11 Gene Contributes to the Risk of Tetralogy of Fallot
Authors: Keavney Bernard , Mamasoula Chrysovalanto , Hall Darroch , Topf Ana , Griffin Helen , Rahman Thahira , Cordell Heather , Goodship Judith ,   UK Congenital Heart Disease Genetics Collaborators
Published: April 2024

Background:
Tetralogy of Fallot (TOF) is the commonest form of cyanotic congenital heart disease. In 80% of cases, TOF behaves as a complex disease exhibiting significant heritability. We investigated whether common genetic variation in 23 candidate genes, selected either because of their expression in the second heart field or their involvement in syndromic congenital heart disease, predisposes to risk of “sporadic”, non-syndromic TOF.

Methods and Results:
207 haplotype-tagging single nucleotide polymorphisms (SNPs) in the candidate genes with minor allele frequencies ≥0.05 were genotyped in a test cohort comprising 362 non-syndromic British Caucasian cases of TOF, and 900 controls (717 unaffected parents of cases, and 183 unrelated healthy people). Six SNPs with suggestive evidence of association (p<0.01) were taken forward for genotyping in a replication cohort comprising 392 cases of TOF, 218 unaffected parents of cases, and 1319 controls. Significant association at p<0.01 was confirmed for one SNP, rs11066320 in the PTPN11 gene, in the replication cohort. Genotype at rs11066320 was associated with a per-allele odds ratio of 1.35 (95% CI 1.20-1.52; p=2.94x10-6) in the total cohort of TOF cases and controls. Genotype at rs11066320 was responsible for a population attributable risk of TOF of approximately 5%. Association between rs11066320 genotype and TOF remained significant after Bonferroni correction for 207 analyses (corrected p=0.00061)

Conclusions:
Common variation in the PTPN11 gene contributes to the risk of non-syndromic TOF.
Abstract 17744: Impact of Hypertensive Crisis on Left Ventricular Systolic and Diastolic Function: Comprehensive Speckle Tracking Strain Analysis vs. Conventional Echocardiography
Authors: Alam Mahboob , Stampehl Mark R , Shahzad Saima A , Siddiqui Sahar , Zhang Lily , Lakkis Nasser M , Dokainish Hisham
Published: April 2024

Introduction:
Echocardiographic strain analysis using speckle tracking is more sensitive than traditional 2-D & Doppler evaluation. The acute impact of hypertensive crisis on LV systolic and diastolic function using echocardiography is not described.

Hypothesis:
Hypertensive crisis induces acute impairment of LV systolic & diastolic function that may be detected using strain analysis.

Methods:
Thirty consecutive patients with hypertensive crisis underwent serial echocardiograms including 2D, Doppler & Speckle Tracking strain analyses at baseline & after blood pressure optimization.

Results:
Mean age of the patients was 53.9 ± 12.8 yrs. Most common presenting symptoms were shortness of breath (70%), chest pain (43.3%), & altered mental status (13.3%). Mean systolic & diastolic blood pressures at baseline were 193.5 ± 25.1mmHg and 106.8 ± 19.8mmHg that reduced to 142.8 ± 20.5mmHg (p<0.001) and 76.7 ± 18.4mmHg (p<0.001) respectively after therapy.Baseline and follow-up echocardiograms showed reduction in left and right atrial volumes at follow-up. There was no change in LV ejection fraction & fractional shortening at follow-up (48.5 ± 18.2 % vs. 46.7 ± 18.3 %; p=0.50 and 28.0 ± 15.2 % vs. 30.8 ± 14.4 %; p=0.22 respectively). Doppler trans-mitral E-wave and A-wave velocities & mitral E/A ratio were similar at baseline and follow-up.There was an increase in mean global longitudinal LV systolic strain (-10.4 ± 4.4 % to -12.1 ± 4.2 %; p=0.011). Peak systolic circumferential strain increased on follow-up from -6.0 ± 3.2 to -11.3 ± 5.4, p=0.03.Mean global early diastolic strain increased from -4.9 ± 2.7 to -9.4 ± 5.0, p=0.05 at follow-up.

Conclusions:
Our study describes the impact of hypertensive crisis on echocardipgrahic parameters of LV systolic and diastolic function using strain analysis that has never been described before. Global longitudinal & circumferential systolic strain are more sensitive at detecting subtle changes in LV systolic function in the setting of hypertensive crisis when compared to ejection fraction and fractional shortening. Echocardiographic indices of LV diastolic function (E/e', Left atrial volume and mitral DT) as well as early diastolic strain also significantly improve after therapy.
Abstract 17905: Aetiological Role of Folate Deficiency in Congenital Cardiovascular Malformation: Evidence From “Mendelian Randomisation” and Meta-Analysis
Authors: Mamasoula Chrysovalanto , Hall Darroch , Pierscionek Tomasz , Topf Ana , Palomino-Doza Julian , Rahman Thahira , Tan Huay , Bentham Jamie , Bhattacharya Shoumo , Cosgrove Catherine , Brook David , Granados Riveron Javier , Bu'Lock Frances , O'Sullivan John , Stuart Graham , Goodship Judith , Cordell Heather , Keavney Bernard
Published: April 2024

Background:
The existence of a causal relationship between lower levels of plasma folate and congenital cardiovascular malformation (CVM) remains contentious. We undertook a genetic approach using the principles of “Mendelian randomization” to determine the causality of folate in CVM risk.

Methods and Findings:
We compared genotype frequencies at the methylene tetrahydrofolate reductase (MTHFR) C677T single nucleotide polymorphism (SNP) in 1186 CVM cases and 4168 controls. The TT genotype at MTHFR C677T is associated with lower plasma folate. Thus, if lower plasma folate had a causal effect on CVM risk, a higher frequency of TT genotype among CVM cases than among healthy controls would be anticipated. We placed our results in the context of a meta-analysis of all previously published studies of this question, which included a further 1883 cases and 3069 controls in 25 studies. We used random-effects models to meta-analyse the data. We conducted sensitivity analyses to examine folate fortification of flour as a potential source of heterogeneity. The primary genotyping data in 1186 cases and 4168 controls revealed a trend towards increased risk with the TT genotype, but this did not reach statistical significance (OR 1.15 [95% CI 0.94-1.40]). Combination of our primary data with previous studies, however, showed association in the complete dataset (OR 1.45 [95% CI 1.12-1.89]; p=0.005) comprising a total of 3069 CVM cases and 7271 controls. Studies conducted in countries without mandatory folate fortification showed an effect of C677T genotype on CVM risk (OR 1.63 [95% CI 1.19 - 2.25]) whereas studies conducted in countries with mandatory fortification did not (OR 0.96 [95% CI 0.64-1.44]). These odds ratios were significantly different from each other (p=0.032).

Conclusions:
We demonstrate genetic evidence in favour of a causal relationship between lower levels of plasma folate and CVM. Moreover, our results suggest that folate fortification abrogates the risk of CVM attributable to folate deficiency.
Abstract 17919: Defibrillation Thresholds in Single Versus Dual Coil ICD Lead Systems: Is There Any Difference?
Authors: Mokabberi Rasoul , Haftbaradaran M. Afsaneh , Pranesh Shruthi , Kumar Anil , Tang Xiaoqin , Storm Randle , Oren Jess , Vijayaraman pughazendhi , Dandamudi Gopi
Published: April 2024

Background:
Single coil implantable cardioverter defibrillator (ICD) lead systems are less often utilized even though no significant difference in defibrillation threshold (DFT) has been demonstrated in comparison to dual coil ICDs. The superior vena cava (SVC) coil is associated with an active fibrotic reaction within the SVC, which can increase complication risk during extraction. We compared DFTs between single vs. dual coil ICD leads at initial implantation.

Methods:
Two hundred and fifty three consecutive patients who underwent new ICD implantation from 9/2008 to 9/2010 at our institution were retrospectively analyzed. Mean follow-up was 14.6±7.3 months.

Results:
Single coil was used more frequently vs. dual coil (172 vs. 81 pts). Age was lower in single coil group (63.0 vs. 72.1, p<0.001). There was no significant difference (single vs. dual coil, p>0.05) in sex, LV EF (28.9 vs. 26.6%), body mass index, ischemic cardiomyopathy, primary prophylaxis indication, procedural complications, lead extraction during follow up, and mortality. DFT testing was performed in 92% and 86% of patients in each group. There was no significant difference in DFTs (16.6±2.8 vs. 17.3±3.2J, p=0.13), DFT safety margin (18.9±3.1 vs. 18.9±3.8J, p=0.96) and successful shocks during follow up between the two groups. The single coil group with ischemic cardiomyopathy had lower DFT (16.1±2.5 vs. 17.9±3.4J, p=0.002), but single coil group with non-ischemic cardiomyopathy had higher DFT (17.7±3.1 vs. 15.9±2.3J, p= 0.03). Right-sided implants in single coil group had lower DFTs (16.4±4 vs. 18.3±2.4J, p=0.008). Two BMI groups (BMI <30 [25±2.5] vs. BMI ≥30 [35.5±4.2]) were analyzed. In BMI <30 group, DFT was lower in single coil group (16.6±3.0J vs. 18.3±3.5J, p=0.008). In BMI ≥30 group, there was no significant difference in DFT between two groups (16.7±2.6 vs. 16.1±2.5, p=0.30).

Conclusion:
Single coil ICD leads offer adequate safety margins in patients with ischemic and non-ischemic cardiomyopathy irrespective of sex, LV function, implant site, and BMI. They should offer a better safety profile during lead extractions.
Abstract 17922: The Impact of Center Volume on One Year Mortality After Orthotopic Heart Transplantation in Elderly Patients
Authors: Kilic Arman , Weiss Eric S , Allen Jeremiah G , Arnaoutakis George J , George Timothy J , Conte John V , Yuh David D
Published: April 2024

Objectives:
Elderly patients are more frequently undergoing orthotopic heart transplantation (OHT) for end-stage heart failure. The aim of this study was to determine the impact of center volume on 1-year mortality following OHT in patients over the age of 60.

Methods:
Data were analyzed from the United Network for Organ Sharing (UNOS) registry. Elderly patients (age≥60) undergoing OHT between 1997-2009 were included. Average annual center volume for OHT in the elderly was calculated. The proportions of 1-year mortality were calculated for those centers with 10 or more average annual transplants and compared to those with less than 10. A multivariate logistic regression model was constructed utilizing significant univariate predictors to evaluate the independent impact of center volume on 1-year mortality.

Results:
A total of 26,818 adult patients underwent OHT during the study period, with 7,087(26.4%) being over the age of 60. Mean annual volume of OHT in elderly patients was 9.5±7.7 transplants. There were 1,073(15.1%) 1-year mortalities and 5,729(80.8%) 1-year survivors, with the remaining 285(4.0%) patients being alive but with follow-up of less than a year. Mean age of included patients was 63.9±3.1 years, with 5,669(83.3%) males. The most common indications for transplantation were idiopathic dilated cardiomyopathy (n=5,803; 85.3%) and coronary artery disease (n=600; 8.8%). The proportion of 1-year mortality was 17.4% in low volume centers (<10 annual transplants) versus 13.1% at high volume centers (p<0.001). In multivariate analysis, low annual center volume significantly increased the odds of 1-year mortality (OR 0.98, 95% CI 0.96-0.99, p<0.001) [see Table].

Conclusions:
In elderly patients undergoing OHT, center volume significantly impacts 1-year mortality. These data strongly suggest that OHT in elderly patients should be performed at centers that have higher volumes in this specific cohort.
Abstract 17947: Large Scale Mouse Mutagenesis Screen Using Fetal Echocardiography Indicates Genetic Contribution to Hypoplastic Left Heart Syndrome and Wide Spectrum of Other Congenital Heart Defects
Authors: Liu Xiaoqin , Francis Richard , Ramirez Ricardo , Chen Guozhen , Subramanian Ramiah , Tobita Kimimasa , Kim Andrew J , Anderton Shane , Kim Youngsil , Wong Li-yin , Tsuchya Maiko , Morgan Judy , Reinholdt Laura , Leatherbury Linda , Lo Cecilia W
Published: April 2024

Introduction:
Large scale forward genetic screens with ethyl-nitroso-urea (ENU) mutagenesis can provide a non-gene biased approach to elucidate the genetic etiology of congenital heart disease (CHD). We are using noninvasive fetal echocardiography to elucidate the genetic etiology of CHD with scanning of 100,000 mouse fetuses to achieve 5 fold genome coverage.

Methods:
C57BL/6J mice (G0) are ENU mutagenized and the resulting G1 males and their G2 daughters are backcrossed to generate G3 fetuses for ultrasound scanning. Primary screening used the clinical Acuson Sequoia ultrasound system with a 15 MHz transducer. Fetuses with CHD were further scanned at 40 MHz with the Vevo 2100 ultra-high frequency biomicroscope (UBM). CHD diagnoses were susbsequently confirmed by necropsy, microCT, and/or histopathology.

Results:
Ultrasound scanning of >20,000 G3 fetuses from >600 G1 pedigrees revealed 4% of fetuses with cardiac defects. A wide spectrum of CHD was observed, including DORV, TGA, PTA, pulmonary/aortic atresia, coarctation, arch anomalies, atrioventricular septal defects (AVSD) and other defects. The most common CHD found was ventricular septal defect. In contrast, hypoplastic left heart syndrome was found in only one mutant line (Figure). We also recovered 10 lines with laterality defects. Heterotaxy mutants exhibited complex CHD, but no heart disease was seen with situs inversus totalis. Overall, the UBM had higher detection sensitivity for cardiac situs (P<0.01), AVSD (P<0.01) and outflow tract malalignment (P<0.01), with 98.3% of the cardiac situs, 91% of the AVSD and 70% of the outflow defects identified by UBM.

Conclusions:
Our studies showed the integration of conventional ultrasound with the UBM for fetal mouse cardiovascular phenotyping can maximize the recovery of CHD mutants. The wide spectrum of CHD observed in our large scale screen indicates the importance of genetic contribution in all varieties of structural heart disease.
Abstract 17998: Continuous Warm Perfusion Reduces Renal Injury During Norwood Operation
Authors: Hammel James M , Lang Haili , Duncan Kim F
Published: April 2024

Objectives:
Perfusion approaches for Norwood include hypothermic circulatory arrest and selective cerebral perfusion. Both techniques result in cold renal ischemia (CRI). Canulation of both the innominate artery and the descending aorta allows maintenance of continuous warm perfusion (CWP) to the kidney and the entire body during arch reconstruction. Renal dysfunction often complicates recovery after complex neonatal cardiac surgery. This review was undertaken to assess the effect of perfusion technique, CRI or CWP, on postoperative renal function.

Methods:
Records of 46 consecutive neonates undergoing Norwood since 2004 were reviewed. The Acute Dialysis Quality Initiative Group RIFLE criteria for renal injury and failure were applied.

Results:
17 patients underwent Norwood with CWP, 29 with CRI. Both median bypass time and median crossclamp time were significantly shorter in CWP than CRI (100 v. 189 min, p = 0.005 and 26 v. 68 min, p < 0.001). Creatinine change from baseline was significantly less in CWP than CRI at 24 and 48 hours (1.19 +/- 0.24 v. 1.58 +/- 0.61, p = 0.02; and 1.58 +/- 0.60 v. 1.16 +/- 0.28, p = 0.01)(see Chart). 1 of 17 CWP patients had renal injury by urine output criteria at 24 hours, compared to 7 of 29 CRI patients (p=0.01). 0 of 17 CWP had renal injury by creatinine change criteria, and 2 of 17 had risk of renal dysfunction, versus 6 of 29 and 12 of 29 CRI respectively (p = 0.006 and p = 0.003). Median fluid balance at 24 hours was +121 ml. for CWP vs. +252 ml for CRI. Renal dysfunction eventually resolved in all patients.

Conclusions:
Patients undergoing Norwood with continuous warm perfusion of the entire body had less transient renal injury. This was reflected in less early positive fluid balance. Early postoperative renal dysfunction can be avoided through this alternative perfusion technique.
Abstract 18000: Mitochondrial Oxidative Stress and Function compared to Lipoprotein Level, Particle Number and Size in an HIV Positive Cohort
Authors: Parikh Nisha I , Gerschenson Mariana , Seto Todd , Chow Dominic , Shikuma Cecilia
Published: April 2024

Introduction:
Dyslipidemia, arising from viral infection, antiretroviral treatment and changes in body composition, is a key metabolic abnormality believed to underlie increased CVD risk among HIV-infected subjects. Oxidative stress and mitochondrial function is linked to atherosclerosis and HIV treatment. We sought to determine the relationship between mitochondrial oxidative stress, function, and standard clinical lipid profile as well as lipoprotein subclass particle number and size among HIV-infected persons.

Study Sample:
HIV infected individuals, age > 40 years and on stable highly activite antiretroviral therapy for > 6 months.

Methods:
We considered the following measures: 1. mitochondrial-specific 8-oxo-deoxyguanine (8-oxo-dG) and 2. mitochondrial OXPHOS NADH dehydrogenase (Complex I) and cytochrome c oxidase (Complex IV) enzyme activity . Plasma total cholesterol, triglycerides, and HDL-C and LDL-C were directly measured. Lipoprotein subclass size and particle number were measured using proton NMR spectroscopy (LipoScience Assay). Unadjusted linear regression analysis was employed to study the association between mitochondrial and lipid parameters. A p-value of <0.05 was considered significant.

Results:
Among 109 HIV-infected persons (mean age 52 years, 14% women, 52% White, 14% Hispanic, 9% Asian), median CD4 count was 511 cell/mm
3
, median HIV RNA was 48 copies/mm
3
(majority with undetectable virus), BMI prevalence >= 25 kg/m
2
was 64%, diabetes 27%, HTN 34% and current cigarette smoking 28%. 8-oxo-deoxyguanine was associated with small HDL (umol/L) (p=0.03) and VLDL particle size (nm)(p=0.03). Complex I activity was inversely associated with VLDL & chylomicron particle number (nmol/L) (p=0.01), small VLDL particles (nmol/L) (p=0.005), LDL particle (total) (nmol/L) (p=0.02), and small LDL particle (total) (nmol/L) (p=0.02). Complex IV was not associated with any lipid parameters. None of the three mitochondrial parameters studied was associated with clinical lipid profile (total cholesterol, LDL, HDL, or triglycerides).

Conclusions:
Mitochondria oxidative stress and function is associated with lipoprotein subclass size and number but not with clinical lipid profile among treated HIV-infected individuals.
Abstract 18001: Shear Stress-Induced Endothelium-Dependent Dilation of Mouse Coronary Arteries is Caveolae-Dependent
Authors: Chai Qiang , Lee Hon-Chi
Published: April 2024

BACKGROUND:
Shear stress-induced dilation (SSD) is an important vascular endothelial function that is impaired in diseases such as diabetes mellitus. Caveolin-1 is the major structural protein required for the formation of endothelial caveolae, where signaling molecules and pathways are assembled. In this study, we hypothesized that SSD of mouse small coronary arteries (MCA) is caveolae-dependent.

METHODS:
MCA (80-130 μm) freshly isolated from WT and Cav-1 knockout (KO) mice were mounted in a vessel chamber, pressurized at 80 mmHg, pre-contracted to 60-80% baseline diameter with endothelin-1, and subjected to physiological levels of shear stress at 25 dyn/cm
2
using a microinjection pump coupled to a pressure servo controller. SSD was measured by videomicroscopy and expressed as % of maximum diameter measured in the absence of Ca
2+
. Donor (intact WT or KO) and detector (WT with no endothelium) vessels were mounted in separate chambers connected by a micropipette. Diabetes mellitus was produced by streptozotocin (STZ) injection.

RESULTS:
SSD of MCA is significantly diminished in KO mice. 25 dyn/cm
2
produced 92.9±1.2% SSD in WT but only 42.0±0.7% in KO (n=10 for both, *p<0.05). Removal of endothelium reduced SSD to 22.3±3.3% in WT and to 14.9±1.3% in KO (n=8 for both, * vs. intact vessels but not WT vs. KO). Inhibition of eNOS (L-NAME), PGIS (Indocin), and CYP monooxygenase (SKF525A) reduced endothelial-dependent SSD by 44%, 34%, and 21% respectively in WT (all * vs control) but had no effect in KO, suggesting deficiency in shear stress-induced generation of vasodilators in KO. This is confirmed by the significant reduction in SSD in detector vessels with KO serving as donors (*42.0±0.7%, n=6 vs. 64.3±6.4% n=4, WT donor). With diabetes, MCA from WT and KO lost the ability for SSD (WT 25.9±2.4%, n=6 and KO 24.4±2.3%, n=5), which was similar to the effects of endothelium denudation.

CONCLUSION:
Integrity of caveolae is critical for endothelium-dependent SSD in MCA. KO endothelium is deficient in shear stress-mediated generation of vasodilators including NO, PGI
2
, and EET. Diabetic MCA have impaired endothelial function with loss of SSD. Caveolae plays a critical role in endothelial signal transduction from shear stress to vasodilator production and release.
Abstract 18026: Comparative Effectiveness of Pci Versus Cabg for Unprotected Left Main Stenosis- Meta Analysis of Randomzed Controlled Trials
Authors: Samad Fatima , Hakeem Abdul , Kim James , Bhatti Sabha , Mohammed Abdul Waheed , Arif Imran , Leesar Massoud , Helmy Tarek
Published: April 2024

Background
The established mode of revascularization for unprotected left main disease is coronary artery bypass grafting (CABG). Percutaneous coronary intervention (PCI) has been increasingly utilized as a viable alternate.

Objectives
We sought to evaluate the comparative effectiveness of PCI vs. CABG for left main disease by collating the evidence from four published randomized controlled trials. Data Sources PubMed, Cochrane Register of Controlled Trials, conference proceedings, and internet-based resources of clinical trials. Study Selection Randomized trials comparing PCI vs. CABG for unprotected left main disease evaluating the outcomes of interest [death, myocardial infarction (MI), stroke, revascularization and their composite (MACE) were included.

Results
Four randomized trials including 1611 participants (809 in PCI arm and 802 in CABG arm) formed the data set. There was no significant difference in the two groups with regards to baseline characteristics. The weighted mean age was 64 years with 70% men and 32% diabetics. The mean SYNTAX score was 26 in both groups. During a mean follow up of 15 months, the incidence of death was 3% in the PCI arm and 4.2% in the CABG arm [RR 0.75 (0.45, 1.25); p=0.27] .Similarly, there was no difference in the incidence of MI [RR 1(0.57, 1.75); p=0.99] or MACE [RR 1.1 (0.8, 1.5); p=0.26]. PCI was associated with a significant reduction in the risk of stroke [0.2% vs. 1.7%; RR 0.22(0.06, 0.76);p=0.02] but a higher risk of revascularization.[RR 2.09(1.49,2.92);p<0.001].There was no heterogeneity found amongst the trials for these endpoints (I2=0%).

Conclusion
This meta analysis of randomized studies demonstrates the safety and efficacy of PCI compared to CABG for left main disease. While there was no difference in mortality, MI or MACE, PCI confered an advantage of significant reduction in the risk of stroke which was balanced by a higher rate of downstream revascularization. PCI could hence be considered a viable option in selected patients.
Abstract 18031: Effects of Rapid Intravenous Ice-Cold Fluids for Patients Treated with Therapeutic Hypothermia
Authors: Matsuzaki Masakazu , Nagao Ken , Soga Taketomo , Nonogi Hiroshi , Yokoyama Hiroyuki , Yonemoto Naohiro
Published: April 2024

BACKGROUND
Animal data has demonstrated that the sooner cooling is initiated after return of spontaneous circulation (ROSC) from cardiac arrest (CA), the better the outcome. Although rapid infusion of ice-cold intravenous (IV) fluids is feasible, safe, and simple method for induction of hypothermia, it is unclear whether technique of ice-cold IV fluids for induction of hypothermia can increase neurological benefit in patients with ROSC after out-of-hospital CA due to shockable rhythm and non-shockable rhythm.

METHODS
The J-PULSE-Hypo was conducted a multi-center observational registry to investigate the effects of therapeutic hypothermia. In this study, we investigated the effects of ice-cold IV fluids in patients divided into initial CA rhythm (shockable rhythm and non-shockable rhythm). The primary endpoint was favorable neurological outcome at hospital discharge.

RESULTS
Of the 452 unconscious adult patients who were treated with therapeutic hypothermia after out-of-hospital CA due to cardiac etiology, 435 who were cooled from 32°C to 34°C using external devices or extracorporeal devices were included; 228 received induction of cooling using rapid infusion of ice-cold IV fluids, including 185 shockable CA and 43 non-shockable CA, and 215 did not receive ice-cold IV fluids, including 156 shockable CA and 59 non-shockable CA. The time interval from ROSC to induction of cooling was shorter in the IV group than in the non-IV group in each CA rhythm (median; 28 minutes vs. 133 minutes in the shockable CA, p<0.0001, 21 minutes vs. 81 min in the non-shockable CA, p<0.0001). The IV group had higher frequency of favorable neurological outcome than the non-IV group in the patients with shockable CA (68.6% vs.57.7%, p=0.036), but the two groups had similar frequency of favorable neurological outcome in the patients with non-shockable CA. Adjusted odds ratios for favorable neurological outcome after the IV group was 1.66 (95% CI, 1.04-2.65) in the patients with shockable CA, and 0.53 (95% CI, 0.20-1.40) in the patients with non-shockable CA.

CONCLUSION
Rapid infusion of ice-cold IV fluids for induction of hypothermia had neurological benefit for patients with shockable CA, but it had not neurological benefit for patients with non-shockable CA.
Abstract 18070: The Significance of Frank-Starling Mechanism in Diastolic Dysfunction
Authors: Kim Chee Jeong , Lee Wang-Soo , Lee Kwang Je , Kim Sang-Wook , Kim Tae Ho
Published: April 2024

Introduction:
The role of Frank-Starling mechanism is well established in systolic left ventricular (LV) function. However, it is unknown whether this law plays a role in diastolic LV function or not. Irregular RR intervals in atrial fibrillation (AF) provide the opportunity for clinical applications of theoretical mechanism. We compared the relation between RR interval and LV performances according to systolic and diastolic functions.

Methods:
A total of 197 patients with AF were screened. Patients with very rapid or slow ventricular rate, significant valvular stenosis or regurgitation, or acute medical conditions were excluded and 136 patients were enrolled. LV outflow peak ejection velocity (Vpe) was adjusted for the effect of pre-preceding RR interval (RR-2) using the logarithmic equation between RR-2 and Vpe. The logarithmic equation between adjusted Vpe and preceding RR interval (RR-1) was calculated in the coordinates with RR-1 from 0.6 to 1 second. From this equation, the ratio of slope to Vpe at RR-1 = 1 second (Slope/Vpe-1) was obtained.

Results:
Patients with normal systolic function and with a history of heart failure (HF, n=37) had a higher slope than those with normal systolic function and without a history of HF (n=72, p=0.04) and a lower slope than those with systolic dysfunction (n=27, p=0.034). Vpe-1 was not different among groups (p=0.85, Figure left). Slope/Vpe-1 showed similar trend with slope and were more powerful to discriminate three groups than the slope. In patients with previous tachycardia induced cardiomyopathy (n=8), the management decreased slope (p=0.006) and Slope/Vpe-1 (p=0.038) without changes in Vpe-1 (p=0.57, Figure right).

Conclusions:
Frank-Starling mechanism plays a significant role not only in systolic function but also in diastolic function. The relation between LV pressure/volume and performance of diastolic dysfunction was between those of normal function and systolic dysfunction.
Abstract 18084: Systematic Analysis of Gene Expression Differences Between Left and Right Atria in Different Mouse Strains and in Human Atrial Tissue
Authors: Piccini Ilaria , Kahr Peter C , Fabritz Larissa , Greber Boris , Schöler Hans , Scheld Hans H , Hoffmeier Andreas , Brown Nigel A , Kirchhof Paulus
Published: April 2024

Background:
Normal development of the atria requires left-right differentiation during embryonic development. Reduced expression of Pitx2c (Paired-like homeodomain transcription factor2, isoform c), a key regulator of left-right asymmetry, has recently been linked to atrial fibrillation. To characterize differences between left and right atrium in adult hearts, we systematically studied the molecular composition of left and right atrial tissue in adult murine and human atria.

Methods:
We compared left and right atrial gene expression in healthy, adult mice of different strains (MF1, 3 months old; MF1, 12 months old; Swiss Agouti, 12 months old) by employing whole genome array analyses on freshly frozen atrial tissue. Selected genes with enriched expression in right or left atrium were validated by RT-qPCR in further animals, and by RT-qPCR and Western blot in shock-frozen left and right atrial appendages of patients undergoing open heart surgery.

Results:
We identified 77 genes with preferential expression in one atrium that were common in all strains and age groups analysed. Independent of strain and age, Pitx2c was the gene with the highest enrichment in left atrium, while Bmp10 (Bone morphogenetic protein 10) showed enrichment in right atrium, consistent with prior reports. Nine selected genes, including Pitx2c, were validated by RT-qPCR in murine tissue, and five orthologous genes in human tissue. Western blot showed a 2-fold left-right ratio in PITX2c protein in adult human atria. Several of the genes and gene groups enriched in left atria have a reasonable biological role for the prevention of atrial pathology including atrial fibrillation, membrane electrophysiology, metabolic cellular function, and regulation of inflammatory cells. Comparison of the array data sets with published array analyses in heterozygous pitx2+/- atria suggested that approximately half of the genes with left-sided enrichment are regulated by Pitx2c.

Conclusions:
Our study reveals systematic differences between left and right atrial gene expression during adulthood and supports the hypothesis that Pitx2c has a functional role in maintaining “leftness” in the atrium in adult mice and humans.
Abstract 18201: PPAR-δ Augments the Interaction Between Platelets and Late EPCs via EDG-2 Signaling Pathway, Leading to Vascular Regeneration
Authors: Han Jung-Kyu , Won Joo-Yun , Kang Jee-Hoon , Lee Jae-Won , Cho Hyun-Jai , Park Kyung-Woo , Kang Hyun-Jae , Oh Byung-Hee , Park Young-Bae , Kim Hyo-Soo
Published: April 2024

BACKGROUND
EDG (endothelial differentiation gene)-2 is a membrane receptor for LPA (lysophosphatidic acid) which is the major lysophospholipid growth factor generated by platelet activation. We focused on the role of EDG-2 in late EPCs and its regulation by PPAR (peroxisome proliferator activated receptor)-δ.

METHODS & RESULTS
We confirmed the expression of EDG-2 in human late EPCs. Interestingly, EDG-2 expression was upregulated by GW501516, a highly selective PPAR-δ agonist treatment. ChIP and promoter assays showed it occurred via direct transcriptional activation. GW501516 or the supernatant of activated platelets which should contain LPA increased the proliferation (BrdU) of late EPCs, and enhanced their provasculogenic functions such as chemotaxis (Transwell), planar migration (scratch wound healing), and tube formation (
in vitro
Matrigel). Co-treatment of GW501516 and the supernatant resulted in synergism. The above effects were reversed by GSK0660 (PPAR-δ antagonist) or Ki16425 (EDG-2 blocker) treatment, but not so much by PDGF neutralizing antibody.
In vivo
Matrigel plug assay, neither late EPCs (10^6/plug) nor activated platelets induced capillary formation. But the combination of them robustly formed capillaries filled with RBCs. GW501516 potentiated their interaction, leading to more capillaries. In a mouse carotid injury model, late EPCs (DiI tagging) showed more homing to injury site 30 minutes after operation by GW501516 treatment. IF staining confirmed their interaction with platelets (CD61). After 14 days, GW501516-treated late EPC group showed more re-endothelization (IHC for CD31) and less neointimal formation. PPAR-δ or EDG-2 siRNA transfection blocked all
in vivo
effects of GW501516.

CONCLUSIONS
Platelets and late EPCs play a key role in vascular regeneration via EDG-2 - LPA axis. PPAR-δ augments the interaction through EDG-2 upregulation, suggesting its agonist as a good therapeutic candidate for ischemic vascular disease.
Abstract 18228: Cost-Effectiveness of New Oral Antiplatelet Agents and Testing Strategies During Early Invasive Management of Acute Coronary Syndrome Patients
Authors: Hillegass William B , Zoghbi Gilbert , Brott Brigitta C , Kilgore Meredith L , Chapman Gregory D , Misra Vijay K
Published: April 2024

BACKGROUND:
Prasugrel has become available with variable adoption across practices. Incremental cost-effectiveness analysis of prasugrel and other future agents relative to clopidogrel may provide rationale guidance for their appropriate use.

METHODS:
A Markov-model with baseline acute coronary syndrome (ACS) health state and subsequent death, nonfatal myocardial infarction, stent thrombosis, urgent revascularization, major bleeding, and malignancy was constructed with 15 one month cycles. Published incremental costs, utilities, and event frequency distributions from randomized trials and series were used to assign transition probabilities and “payoffs” as a function of time. A second model examined modification of therapy at critical time-points based on genetic and platelet function testing assays. Probabilistic 95% confidence intervals were calculated using the parameter distributions in the model.

RESULTS:
In ACS patients undergoing an early invasive strategy, prasugrel was dominant over clopidogrel with $9,988+/-2,148 saved per QALY saved in the first month after the index event. In months 2 through 15, prasugrel 10 mg daily had incremental estimated cost of $5,820 +/- 2,136 per QALY saved. In months 2 through 15, prasugrel had estimated incremental cost-effectiveness of $42,225 +/-12,499 per QALY saved compared to generic clopidogrel (at lowest current online overseas price.) A strategy of early routine prasugrel administration in all eligible patients followed by genetic testing for loss-of-function CYP450-2C19 gene alleles to guide maintenance therapy was the most cost-effective strategy reducing overall societal cost by 36 +/- 18% with little compromise in net clinical outcomes.

CONCLUSIONS:
The estimated cost-effectiveness of oral antiplatelet adjunctive therapy in ACS patients being managed with an early invasive strategy is time-dependent and optimized by genetic testing. This analysis might help guide rationale selection of oral antiplatelet therapy, reducing arbitrary practice variation.
Abstract 18255: Atrial Fibrillation in RyR2-R2474S Mice
Authors: Xie Wenjun , Shan Jian , Reiken Steven , Chen Bi-Xing , Marks Andrew
Published: April 2024

Background:
Atrial fibrillation (AF) is one of the most common arrhythmias. Despite a wealth of information on the electrical abnormalities present in the working atrial muscle, a detailed understanding of the cellular events that underlie AF is lacking.

Methods:
To explore the role of ryanodine receptor (RyR2) in triggering AF, we executed in vivo intra-esophageal burst pacing induced AF and in vitro atrial myocyte SR Ca2+ leak measurements in WT and RyR2-R2474S+/- mice.

Results:
With the in vivo stimulation protocol, 70% of RyR2-R2474S+/- mice could be stimulated into AF whereas WT mice showed no AF (WT: n = 33, R2474S: n = 10, P < 0.05). Confocal Ca2+ imaging in isolated atrial myocytes from these mice showed that atrial myocytes from RyR2-R2474S+/- mice exhibited a 152% increase in SR Ca2+ leak compared to WT (WT: n = 25, R2474S: n=20, P < 0.01). Further, pretreatment of RyR2-R2474S+/- atrial myocytes for 2 hours with 10 µM S107, a 1,4-benzothiazepine derivative that stabilizes RyR2 by inhibiting depletion of the stabilizing subunit calstabin2 (FKBP12.6) from the RyR2 channel (thereby reducing SR Ca2+ leak), resulted in a 68% decrease in diastolic SR Ca2+ leak AF (n = 23, P < 0.05). Administration of S107 treatment via drinking water (20mg/kg/day) for two weeks in RyR2-R2474S+/- mice prevented burst pacing induced-AF (from 70% to 0%) (n = 10 in both groups, P < 0.05).

Conclusions:
Thus, SR Ca2+ leak via RyR2 plays a critical role in the pathogenesis of AF and may be a novel therapeutic target for AF in humans.
Abstract 18256: Importance of Controlling Dietary Intake of Saturated Fat for Prevention of Coronary Heart Disease: Lessons From the Metabolic Ward Studies
Authors: Clarke Robert , Hopewell Jemma C
Published: April 2024

Background:
Recent studies of dietary fat and coronary heart disease (CHD) have questioned the relevance of limiting the intake of saturated fatty acids (SFA) for prevention of CHD.

Objective:
To re-examine the metabolic ward trials assessing the effects on plasma levels of LDL-C or of high-density lipoprotein cholesterol (HDL-C) of replacement of dietary intake of SFA, trans fats (TFA) and dietary cholesterol by PUFA, monounsaturated fats (MUFA) or by carbohydrate.

Methods:
In a meta-analysis of 103 metabolic ward studies involving 500 controlled dietary trials, the effects on plasma levels of total cholesterol, LDL-C, HDL-C and total/HDL-C ratio of isocaloric replacement of calories as SFA or TFA by PUFA, MUFA or carbohydrate were assessed using multivariate regression analysis.

Results:
Higher intakes of SFA, dietary cholesterol and TFA were each significantly associated with higher LDL-C levels, but higher intakes of PUFA were associated with lower LDL-C, and MUFA had no effect on LDL-C. Isocaloric replacement of TFA (2% calories) by PUFA had twice the effect on total/HDL ratio than by carbohydrate (-0.13 [0.03] vs -0.07 [0.02]). By contrast, isocaloric replacement of 5% of calories as SFA by PUFA had a much greater effect on both LDL-C and on the total/LDL-C ratio than the elimination of TFA. Taken together, isocaloric replacement of SFA (5% calories), TFA (2% calories) and dietary cholesterol (100 mg) by PUFA should lower LDL-C by about 0.5 mmol/L (20 mg/dL) and the total/HDL-C ratio by 0.33.

Conclusions:
Excessive intakes of SFA remain a major public health problem and public health strategies for prevention of CHD should not neglect the importance of limiting SFA intake which will result in a greater reduction in LDL-C than the elimination of TFA alone.
Abstract 18280: Mechanosensitive Trpv4 Channels Mediate Cardiac Myofibroblast Differentitation
Authors: Adapala Ravi , Luther Dan , Shah Supriya , Meszaros J Gary , Chilian William M , Thodeti Charles K
Published: April 2024

Cardiac fibroblasts play critical role in cardiac remodeling and during development. Cardiac remodeling following myocardial infarction involves the migration, proliferation and differentiation of cardiac fibroblasts into hypersecretory myofibroblasts. Myofibroblasts facilitate wound repair in the myocardium by secreting and organizing extra cellular matrix (ECM) and fibrosis. However, the molecular mechanisms involved in myofibroblast differentiation are not well known. Because the infarcted/ischemic myocardium is known to undergo mechanical stretch and the muscle phenotypic modulator TGF-β is also increased in ischemia, we hypothesized the mechanotransduction and TGF-β signaling pathway play active role in the differentiation of cardiac fibroblasts to myofibroblasts. Here, we show that the mechanosensitve ion channel TRPV4 is required for TGF-β-induced differentiation of cardiac fibroblasts into myofibroblasts. We found that, the TRPV4-specific antagonist, AB159908 significantly inhibited TGFβ-induced differentiation as measured by incorporation of α-SMA in actin stress fibers (p < 0.05). In contrast, AB159908 did not affect the proliferation of cardiac fibroblasts. Importantly, calcium imaging experiments with Fluo-4 revealed that TGF-β treated fibroblasts exhibit enhanced TRPV4-dependent calcium influx compared to untreated controls (3 fold; p< 0.05). Further, we found that TGF-β-induced myofibroblast differentiation is regulated by the variations in ECM elasticity in a TRPV4 dependent manner. Finally, TGF-β induced myofibroblast differentiation is significantly reduced in cardiac fibroblasts from TRPV4 KO mice compared to controls. Taken together these results suggest, for the first time, that a mechanosensitive ion channel, TRPV4 regulates cardiac fibroblast differentiation to myofibroblasts which could be used as a novel therapeutic target for the treatment of ischemia and myocardial infarction.
Abstract 18282: Use of Percutaneous External Circulatory Support in Patients Undergoing Ventricular Tachycardia Ablation - a Multicenter Experience
Authors: Lakkireddy Dhanunjaya , Vanga Subba Reddy , Bunch Jared , Dendi Raghuveer , Day John , Mahapatra Srijoy , Di Biase Luigi , Burkhardt David , Dawn Buddhadeb , Natale Andrea
Published: April 2024

Introduction:
Recurrent ventricular tachycardia (VT) in patients with cardiomyopathy and advanced heart failure contributes significant morbidity and mortality. Defibrillator shocks and hemodynamic compromise present a greater therapeutic challenge. VT ablation is challenging in these pts and outcomes using hemodynamic support systems is lacking.

Methods:
From a multicenter prospective database, all patients who underwent radiofrequency (RF) ablation for VT between 2006 and 2010 were studied. Pts requiring hemodynamic support during ablation were identified. Inclusion criteria were - clinical hemodynamic instability, unstable VTs and/or poor LVEF(<20%). Patients were grouped into 3 groups based on the type of hemodynamic support (operator choice), group 1 (Impella), group 2 (balloon pump) and group 3 (TandemHeart).

Results:
A total of 31 patients (65 ± 11yrs, 29 (94%) Caucasians, 29(94%) male) were studied. Group1 had 3, group 2 had 9 and group 3 had 19 patients. The baseline, past medical and medication histories including antiarrhythmic drugs were similar. Overall, the mean LVEF was 25±13 and 23 (74%) had non-ischemic cardiomyopathy. On average, 3.87 ± 1.82VTs were induced during ablation and in 26 (84%), clinical VT was induced. Overall acute success rate was 26 (84%), short-term mortality was 5 (16%) and mortality at 12 month follow-up was 6 (19%). Major complications noted in 10 (32%). Significant acute success rate (100%) was noted in group 2 (Balloon pump) while mortality is lower in group 1 (Impella). (Figure1).

Conclusion:
Our study showed significant mortality benefit when a hemodynamic support is used in patients with hemodynamically unstable VT when compared to historical outcomes. In subgroup analysis, Impella group showed improved mortality. However, no major derivations can be made about the superiority of one device over the other due to the relative smaller numbers.
Abstract 18292: Storm Preparations: Use of Carotid Ultrasound for Assessment of Atherosclerotic Disease
Authors: Johri Amer M , Noel Martin , Matangi Murray , Simpson Chris
Published: April 2024

Background:
A call of warning was raised by scientists at the 2010 American Heart Association meeting: “Cardiovascular Disease in the Elderly is the Coming Tsunami.” Accordingly, the need to develop imaging modalities to detect coronary artery disease (CAD) early was identified. Carotid intimal medial thickening (CIMT) may serve as a systemic barometer of atherosclerosis throughout the arterial tree. Plaque is also often observed in the carotid arteries of patients however its association with CAD is unclear. Our objective was to determine the sensitivity and negative predictive value of CIMT and carotid plaque in consecutive outpatients referred for angiography.

Methods:
Carotid scans were conducted immediately following the angiogram in 242 consecutive outpatients. An ultrasonography device (General Electric Vivid 7; USA) equipped with a 10 MHz linear probe was used to record images from both the right and left carotid arteries. CIMT in the distal common carotid artery and the maximal two-dimensional thickness of carotid bulb plaque was measured. The angiogram was scored as 0 (no coronary lesions), 1 (mild coronary atherosclerosis), 2 (at least 50% narrowing in one vessel), and 3 (at least 50% narrowing in two or more vessels). Sensitivity and negative predictive value of CIMT < 1mm and of plaque < 1.5 mm was determined for an angiogram score of 0 or 1.

Results:
The prevalence of significant CAD in this population was 71%. The average CIMT for men was 0.94 +/− 0.22 mm and for women was 0.88 +/− 0.19 mm. The mean maximum plaque value was 2.31 +/− 0.95 mm for men, and 2.03 +/− 1.01 mm for women. Plaque thickness but not CIMT was greater in patients with CAD (p< 0.001). The negative predictive value of CIMT was poor (< 50%) however the sensitivity and negative predictive value of plaque was 94 and 75 % respectively.

Conclusion:
A complete carotid ultrasound that includes plaque assessment may serve as an inexpensive and low-risk test to help rule out CAD in outpatients.
Abstract 18304: Dimerization with the Prostacyclin Receptor Triggers Thromboxane Receptor Relocation to Lipid Rafts
Authors: Ibrahim Salam , Smyth Emer
Published: April 2024

Membrane rafts are liquid-ordered microdomains characterized by high levels of sphingolipids, cholesterol and saturated phospholipids. Prostacyclin (PGI2) effects its anti-thrombotic, anti-proliferative and vasodilator actions via a Gs coupled receptor, IP, opposing those of thromboxane A2 (TxA2) via TP, a Gq coupled receptor. IP is raft localized but the relevance is ill-defined. We reported a TP signaling shift to IP-like function through IP-TP heterodimerzation. In the present study, we examined IP and TP membrane localization and explored the importance of raft integrity to receptor dimerization and function. COS-7 cells were co-transfected with IP and/or TP. Gs activation was examined by measuring cAMP stimulation with cicaprost (PGI2 analog) or U46619 (TxA2 analog). Membrane localization was examined by measuring bioluminesence resonance energy transfer (BRET) from IP or TP fused to renilla luciferase (rLuc) to a raft-associated fluorophore, DiIC16. IP was localized in rafts, identified as saturable BRET from rLucIP to DiIC16. By comparison, rLucTP transfer was shallow and inefficient, similar to the non-raft associated ß2-adrenoreceptor, consistent with raft exclusion. Interestingly, the rLucTP BRET curve was strongly left-shifted, readily saturable and indistinguishable from rLucIP alone, when rLucTP-cells were cotransfected with untagged IP. This indicated IP-triggered relocation of TP to lipid rafts. Disruption of rafts by cholesterol depletion (2-hydroxypropyl-β-cyclodextrin; 20mM, 1hr) reduced cicaprost-stimulated cAMP in IP transfected cells (48.49±9.18 % inhibition) as well as cicaprost- and U46619-stimulated cAMP in IP-TP co-transfected cells (51.18+10.47 and 52.78+6.83 % inhibition) consistent with IPTP heterodimer function in rafts. Our data confirm IP localization to, and TP exclusion from, membrane rafts. IP function alone and as part of the IPTP heterodimer was at least partially dependent on raft integrity. Further, the shift in TP signaling to the cAMP pathway likely follows its relocation to rafts as the IPTP heterodimer. These data highlight the intricate cellular mechanisms through which IP can limit the cardiovascular effects of TP activation contributing to cardiovascular homeostasis and disease.