bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 17135: Distribution of Anti-oxidative Activity During Remodeling of High Density Lipoprotein: Studies With CSL112
Authors: Cukier Alexandre M , Diditchenko Svetlana A , Navdaev Alexei V , Spycher Martin O , Chapman M J , Wright Samuel D , Kontush Anatol
Published: July 2021

We have previously shown that reconstituted HDL has the ability to inactivate phospholipid hydroperoxides (PLOOH) in oxidized LDL by virtue of redox-active Met residues present in apolipoprotein A-I (apoA-I), with the level of activity being proportional to the amount of apoA-I protein added. CSL112 is human apoA-I, reconstituted with phosphatidylcholine to form HDL particles suitable for infusion. Infusing CSL112 into human subjects or adding it to human plasma ex vivo, causes remodeling of endogenous HDL. Similar remodeling occurs upon incubation of CSL112 with purified HDL3 and results in accumulation of three HDL species: enlarged HDL (HDL2), a smaller, dense species (HDL3c-like), and lipid-poor apoA-I (pre-β1 HDL). Here we examine the distribution of anti-oxidant activity upon remodeling of native plasma HDL induced by CSL112.

We incubated CSL112 with human plasma HDL3, isolated the three populations of remodeled HDL particles by density gradient ultracentrifugation and compared (on a total protein basis) their ability to inactivate PLOOH derived from oxidized LDL as well as their apoA-I content of unoxidized and oxidized Met residues.

Both parent CSL112 and HDL3 displayed anti-oxidative activity, inactivating 22±4 and 47±9% of PLOOH, respectively (n=4). Upon remodeling, this activity was mainly found in enlarged HDL2 and smaller HDL3c-like species (PLOOH inactivation, 46±3 and 47±9%, respectively) and was low (23±17%) in lipid-poor apoA-I. In parallel, apoA-I Met residues were oxidized in HDL; oxidation was several fold lower in the lipid-poor apoA-I (12±3%) compared to larger species (62±1% and 69±2% in HDL2 and HDL3c-like particles), consistent with a limited accessibility of apoA-I Met to PLOOH molecules in the lipid-poor particles.

These studies further confirm the unequal distribution of HDL function among HDL subclasses and emphasize the important role of HDL remodeling in the production and maintenance of HDL functionality. The antioxidant properties of CSL112 add to its potential as a promising therapy for reducing the high risk of early recurrent atherothrombotic events following acute MI (AMI). A Phase IIb trial (AEGIS-I; NCT02108262) of CSL112 in AMI patients is ongoing.
Abstract 17147: No Changes in Average Lipid Profiles in the United States From 2003 to 2012: The National Health and Nutrition Examination Survey 2003-2012
Authors: Toth Peter P , Palmer Michael K , Henriksson Karin M
Published: July 2021

Introduction:
Lipid-lowering therapies (LLT) are now regularly used in the management of dyslipidemia, but it is not known how the increased use of LLT has influenced lipid levels of the US population. We determined the average lipid profiles of the US population from 2003-2012 in the National Health and Nutrition Examination Survey (NHANES).

Methods:
Coronary heart disease risk using NCEP ATP III criteria was assessed in adult participants in 2-yearly NHANES surveys from 2003-2004 to 2011-2012. Fasting serum values were used to determine lipid profiles of men and women in each risk group. The proportion of participants in each risk group receiving LLT was also calculated.

Results:
Estimates for the US population were based on 11,256 observations in NHANES from 2003-2012. From the 2003-2004 survey to the 2011-2012 survey, a significant increase in the use of LLT was observed in the low- (6% to 11%; p<0.0001) and high-risk (41% to 52%; p=0.008) groups. A possible trend for reduction in median triglyceride (TG) levels was observed in women in the high-risk group only, from 170 mg/dL (2003-2004) to 127 mg/dL (2011-2012). However, sample sizes are small (165-248 participants), and variability is high; therefore, this may impact on the applicability of the TG results. For both men and women and in all risk categories, no obvious trend for change in mean levels of non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and HDL-C was observed (Figure). Mean HDL-C levels were higher in women than in men in all risk groups, consistently over the time period (Figure).

Conclusion:
Despite an increase in the use of LLT, we observed no trend for change in lipid profiles in low-, intermediate- or high-risk men and women in the US population. This may be due to the variability in response to LLT, and highlights the need for more aggressive identification and treatment of high-risk individuals, as recommended in the ACC/AHA guideline.
Abstract 17169: The Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial
Authors: Bohula Erin A , Giugliano Robert P , Ruff Christian T , Kuder Julia F , Murphy Sabina A , Antman Elliott M , Braunwald Eugene
Published: July 2021

Background:
Edoxaban (edox), an oral factor Xa inhibitor with 50% renal clearance, was non-inferior to warfarin for prevention of thromboembolic events and significantly reduced bleeding in pts with AF. However, a detailed analysis of the impact of creatinine clearance (CrCl) on clinical outcomes with edox has not been described.

Purpose:
We evaluated the safety, efficacy and net clinical outcome of edox vs warfarin (warf) across the range of baseline CrCl in the ENGAGE AF-TIMI 48 trial.

Methods:
14,071 AF pts at moderate-to-high risk of stroke were randomized to edox 60mg QD or warf. Severe renal dysfunction (CrCl<30ml/min) was exclusionary and a CrCl 30-50 resulted in a 50% dose reduction of edox (30mg QD). Endpoints of stroke or systemic embolism (SSE), ISTH major bleeding (MB) and the primary net clinical outcome of SSE/MB and all-cause mortality (ACM) were evaluated by intention-to-treat analysis by the pre-specified singular CrCl cutpoint of 50ml/min and additional exploratory cutpoints.

Results:
The relative risk of SSE with edox vs warf in the pre-specified analysis in those with CrCl≤50 (HR 0.87, 0.65-1.18) was similar to those with CrCl>50 (HR 0.87, 0.72-1.04; p-int=0.94). Evaluation by more granular, exploratory cutpoints demonstrated higher rates of SSE (Fig 1a; p-int<0.001) and ischemic stroke (p-int=0.05) with edox vs warf in the upper range of CrCl, but lower rates of bleeding were observed at all levels of CrCl with edox (Fig 1a; p-int=0.39). For the net clinical outcome (SSE/MB/ACM), there was no significant difference between edox and warf at higher levels of renal function due to the preserved effect on bleeding and mortality (Fig 1b; p-int 0.17). An on-treatment analysis with plasma drug levels will be shown.

Conclusion:
While there is a trend towards decreasing efficacy with increasing CrCl for edox compared to well-managed warfarin, the overall safety and net clinical benefit of edox compared to warfarin is consistent across renal function groups.
Abstract 17174: Comparative Economics of Transcatheter and Surgical Aortic Valve Replacements in Medicare Patients
Authors: McCarthy Fenton H , McDermott Katherine M , Kini Vinay U , Herrmann Howard C , Bavaria Joseph E , Anwaruddin Saif , Giri Jay , Szeto Wilson Y , Groeneveld Peter W , Desai Nimesh D
Published: July 2021

Objectives:
To describe the economics of transcatheter aortic valve replacement (TAVR) in the US, and to compare costs and payments for TAVR with surgical aortic valve replacement (SAVR) in the context of expanding clinical indications for TAVR.

Methods:
Hospital charges and Medicare payments from Medicare claims for patients undergoing SAVR or TAVR between January and December 2012. Medicare payments represent actual payments to hospitals accounting for transfer penalties. Cost-to-charge ratios were used to estimate hospital costs from charges. Costs and payments were examined in propensity score matched TAVR and SAVR patients.

Results:
Medicare spent $215,770,218 nationally for TAVR in 2012, the first year of commercial implantation. Hospital costs were significantly higher for TAVR (median $50,200; interquartile range (IQR) $39,800 - $64,300) than SAVR ($45,500; $34,500 - $63,300; p <0.01) largely due to higher estimated medical supply costs, which includes the implanted valve prosthesis (Table 1, Figure 1). Medicare payments were lower for TAVR ($50,100; $37800 - $65400) than for SAVR hospitalizations ($51,200; $38,300 - $66,700; p<0.01). Median difference between payments and costs was -$3380 for TAVR and $2390 for SAVR hospitalizations (p<0.01). For hospitals to break even on TAVR, overall costs need to decrease by 7% or isolated medical supply costs (primarily related to the TAVR valve) by 22%.

Conclusions:
Among patients of similar risk, TAVR was associated with higher hospital costs despite shorter ICU and hospital stays compared to SAVR. Overall and/or medical device cost reductions are necessary for TAVR to have a net neutral financial impact on hospitals.
Abstract 17202: Comparative Performance of the R
2
Chads
2
, Chads
2
, and Cha
2
Ds
2
-vasc Scores in Atrial Fibrillation
Authors: O'Brien Emily C , Simon DaJuanicia N , Thomas Laine , Fonarow Gregg C , Kowey Peter R , Mahaffey Kenneth W , Piccini Jonathan P , Peterson Eric D
Published: July 2021

Background
. Existing scores to estimate stroke risk in atrial fibrillation (AF) have shown variable performance. We compared the predictive performance of the R
2
CHADS
2
score, which includes a term for renal dysfunction, to that of two existing stroke risk scores, CHADS
2
and CHA
2
DS
2
-VASc.

Methods
. We used data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF in patients >18 years. We examined the association between impaired renal function (CrCl<60 mL/min) and 2-year risk of stroke/systemic embolism (SE) in separate Cox proportional hazards models with linear terms for CHADS
2
and CHA
2
DS
2
-VASc scores. We compared discrimination of the three scores using c-indices and evaluated calibration of R
2
CHADS
2
by comparing event rates in ORBIT to published rates from an external clinical trial population (ROCKET-AF) and an observational cohort (ATRIA).

Results
. We included N=9743 patients enrolled at 174 ORBIT-AF sites. The median age was 75 years (IQR 67-82), 89.5% were white, 42.5% were female, and 76.4% were taking oral anticoagulation (OAC). Over a median follow-up of 2 years, N=214 stroke/systemic embolism (SE) events occurred (1.00 per 100 pt.-years). Impaired renal function was present in 35.4% of patients and was associated (HR; 95% CI) with increased stroke/SE risk in unadjusted models (1.65; 1.27-2.14). This association was attenuated in models adjusting for CHADS
2
(1.21; 0.92, 1.60) or CHA
2
DS
2
-VASc (1.05; 0.79, 1.40). Discrimination (c-index; 95% CI) was similar for R
2
CHADS
2
, CHADS
2
and CHA
2
DS
2
-VASc; results were consistent by baseline OAC use (Table). Stroke/SE event rates in ORBIT were lower than those in two external populations for all levels of R
2
CHADS
2
.

Conclusion:
In a well-treated community patient population, renal dysfunction did not improve discrimination of traditional embolic risk models. Future studies examining the association between renal dysfunction and outcomes by type of OAC are needed.
Abstract 17205: Polypharmacy and the Impact of Apixaban on Clinical Events in Patients With Atrial Fibrillation: Insights From the ARISTOTLE Trial
Authors: Jaspers Focks Jeroen , Brouwer Marc A , Wojdyla Daniel M , Tomas Laine , Lopes Renato D , Hanna Michael , Lanas Fernando , Xavier Denis , Husted Steen , Wallentin Lars , Alexander John H , Granger Christopher B , Verheugt Freek W
Published: July 2021

Purpose:
Polypharmacy is associated with frailty and adverse clinical events. Compared with warfarin, apixaban is more efficacious in preventing stroke and safer in patients with atrial fibrillation (AF). However, it has not been shown if these benefits are preserved in patients treated with several concomitant drugs.

Methods:
All patients included in the ARISTOTLE trial (n=18,201) were divided into tertiles according to the number of drugs used at baseline. The treatment effects of apixaban versus warfarin on clinical outcomes were assessed according to the number of concomitant medications.

Results:
The median number of concomitant drugs was 6 (IQR 5-9). When comparing tertiles, patients using more drugs were older, more often female, and had more comorbidities than patients using less medications. During a median follow-up of 1.8 years, the rates of efficacy and safety outcomes increased across tertiles. The superiority of apixaban when compared with warfarin in reducing stroke and systemic embolism was consistent regardless of the number of concomitant drugs (interaction p-value= 0.8203; Table). In terms of safety, the magnitude of benefit with apixaban decreased with the number of drugs taken (interaction p-value= 0.0173). A similar treatment effect pattern was seen for the net clinical benefit.

Conclusions:
In ARISTOTLE, both ischemic and hemorrhagic complications occurred more frequently in patients treated with a higher number of concomitant medications. The benefits of apixaban in reducing stroke were preserved, regardless of the number of drugs taken. In terms of safety and net clinical benefit, while the rates were consistently lower with apixaban, the magnitude of benefit with apixaban decreased with the number of concomitant drugs. Thus, apixaban is a more effective and at least as safe alternative to warfarin in patient with AF with polypharmacy.
Abstract 17232: Comparison of Methods for the Measurement of Cholesterol Efflux Capacity of Plasma HDL With J774 Mouse Macrophages Reveals Superiority of the Radioactive Cholesterol Method over the BODIPY-Cholesterol-2 Method
Authors: Rhainds David , Julien Renaud , Marie Boulé , Maxime Denis , Eric Rhéaume , Jean-Claude Tardif
Published: July 2021

Recent clinical studies suggest that raising HDL-cholesterol (HDL-C) concentration is insufficient to lower cardiovascular risk and that protection derives from other characteristics of HDL particles. One such characteristic that can be measured in vitro is the cholesterol efflux capacity of plasma, an assay where HDL accepts labelled cholesterol from macrophages. Recently, a method for the measurement of cholesterol efflux with a fluorescent tracer, BODIPY-cholesterol-2 (BC2), has been proposed as an alternative to the radioactive method. We undertook a systematic comparison of BC2 and 3H-cholesterol methods with J774 macrophages in basal and cAMP-stimulated conditions with purified acceptors, plasma from healthy volunteers and patients with myocardial infarction of the Montreal Heart Institute Biobank. Dose-response curves show higher affinity of BC2 vs. 3H cholesterol with apoA-I, HDL and apoB-depleted plasma (all p<0.01) and a higher maximal efflux for HDL and depleted plasma (both p<0.001) in stimulated conditions. This was reflected in a faster kinetics of BC2 efflux compared to 3H-cholesterol efflux (time for half-maximal efflux 4.1h vs. 10.2 h) and resulted in a 2.5-fold increase of BC2 maximal efflux (p<0.01). With 50 normolipidemic plasmas (2.8%, 4h efflux), the two methods were not correlated in basal conditions (r2=0.079) and strongly correlated in stimulated conditions (r2=0.830). BC2 values did not correlate with HDL-C in all conditions, contrary to 3H cholesterol values (p<0.01). Using more complex samples from patients with MI (n=115), the correlations were modest in basal (r2=0.219) and stimulated (r2=0.400) conditions. Differences between controls and MI cases showed reduced significance with BC-2 compared to 3H cholesterol. Lastly, in macrophages examined under the confocal microscope, BC2 labels vesicular structures colocalized with filipin, a free cholesterol marker, suggesting endosomal loading of BC2. Thus, the BC2 method is not equivalent to the classic 3H cholesterol method for cholesterol efflux measurement.
Abstract 17285: Frequent Consumption of Meals Prepared at Home and Risk of Type 2 Diabetes Among American Men and Women
Authors: Zong Geng , Eisenberg David M , Hu Frank B , Sun Qi
Published: July 2021

Introduction:
The frequency of eating meals prepared at home (MPAH) decreased among Americans over the last 50 years. Eating out has been associated with poor diet quality and weight gain in adolescents and adult. Few studies have examined MPAH frequency in relation to diabetes risk.

Hypothesis:
Having MPAH is associated with lower risk of Type 2 Diabetes (T2D).

Methods:
We followed 57,994 women in the Nurses’ Health Study and 41,679 men in the Health Professionals Follow-up Study from 1986 to 2012. Participants were free of diabetes, cardiovascular disease, and cancer at baseline. Weekly frequencies of consuming MPAH were collected at baseline, and summed up as overall MPAH.

Results:
Participants with more MPAH had higher intake of whole grains, total and low-fat dairy products, fruits, and vegetables, and lower sugar sweetened beverage (SSB) at baseline. However, MPAH turned to be associated with more red meat and low coffee intakes. MPAH was moderately associated with less weight gain during follow-up. Compared to those with 0-6 overall MPAH/week, women with 11-14 MPAH/week had 0.45±0.08kg less weight gain over 8 years, whereas men had 0.41±0.07 kg less weight gain (P<0.001) for the same comparison. During 2.3 million person-years of follow-up, 8959 T2D cases were identified and confirmed in both cohorts. After multivariate adjustment of demographic and lifestyle factors, pooled hazard ratio (95% confidence interval) of T2D were 0.96 (0.90, 1.01), 0.96 (0.87, 1.06), 0.88 (0.83, 0.94) for participants who had 7-8, 9-10, and 11-14 MPAH/week (P for trend<0.001), comparing with those eating 0-6 MPAH/week. Each additional MPAH for lunch was associated with 2% lower risk of T2D, whereas the corresponding value was 4% for dinner (P<0.001 for both). These findings were attenuated when BMI or SSB were further adjusted: the hazard ratio comparing participants with 11-14 MPAH/week to those with 0-6 MPAH/week were 0.95 (0.90, 1.01; P for trend=0.13) with adjusting of BMI, and 0.94 (0.89, 1.00; P for trend=0.09) with adjustment of SSB.

Conclusions:
These findings suggest that eating more MPAH is associated with a lower risk of T2D overtime, and this relationship may be partly ascribed to less weight gain and lower SSB intake by those who prepare their own meals at home more often.
Abstract 17301: Functional Characterization of KCNK3 Mutants Associated With Pulmonary Arterial Hypertension Under Physiologically Relevant Heterozygous Conditions
Authors: Bohnen Michael S , Roman-Campos Danilo , Terrenoire Cecile , Jnani Jack , Chen Lei , Sampson Kevin S , Chung Wendy K , Kass Robert S
Published: July 2021

KCNK3 encodes a two-pore domain K+ channel, TASK-1, which is inhibited by extracellular acidity and hypoxia. Expressed in a variety of tissues, including human pulmonary artery smooth muscle cells (hPASMCs), the central nervous system, pancreas, and adrenal glands, TASK-1 contributes to the resting membrane potential of cells in which it is expressed. Recently, our group reported mutations in KCNK3 underlying idiopathic pulmonary arterial hypertension (PAH), resulting from loss of TASK-1 function, partially pharmacologically rescuable with ONO-RS-082. TASK-1 dimerizes in vivo, forming functional channels with another TASK-1 subunit or with the related TASK-3 channel. TASK-1 and TASK-3 often are expressed in the same cells, although it has been reported that TASK-1 alone is expressed in the lung. Our initial study examined mutant and wildtype (WT) homodimeric TASK-1 channels expressed heterologously in COS-7 cells. Here we further characterize PAH-linked TASK-1 mutations in physiologically relevant heterozygous conditions in COS-7 and hPASMC cell lines. We engineered heterodimeric channels consisting of one mutant and one WT subunit; compared this with co-expression of mutant and WT channels; and measured channel activity with whole cell patch clamp procedures. We found a mutation specific impact of heterozygosity on channel activity. One mutation, V221L, produces a shift in pH dependence accounting for loss of function at physiological pH 7.4, partially rescued by dimerization with a WT subunit, while another, G203D, produces near complete loss of function as a homo- or hetero-dimer. The presence of TASK-3 results in greater rescue of V221L TASK-1 activity at pH 7.4 than does WT TASK-1. Additionally, under current clamp we found that ONO-RS-082 hyperpolarizes the membrane potential in hPASMCs expressing WT or V221L TASK-1, reversible by selective block of TASK-1 with ML365. Together, our results suggest (a) TASK-1 mutant heterodimers exhibit loss of function with mutation specific severity; (b) TASK-3 may rescue mutant TASK-1 and underlie a tissue specific impact of the TASK-1 mutations observed clinically; and (c) PAH TASK-1 mutants can be pharmacologically modulated in hPASMCs and alter the critically important resting membrane potential.
Abstract 17304: Sudden Cardiac Death After Acute Heart Failure Hospitalization: Insights From ASCEND-HF
Authors: Pokorney Sean , Al-Khatib Sana M , Sun Jie-Lena , Schulte Phillip , O'Connor Christopher M , Teerlink John R , Armstrong Paul W , Ezekowitz Jusitn A , Starling Randall C , Voors Adriaan A , Velazquez Eric C , Hernandez Adrian F , Mentz Robert J
Published: July 2021

Introduction:
Despite concerns about sudden cardiac death (SCD) early after acute heart failure (AHF) hospitalization, the incidence of SCD and the factors and associated with its occurrence have not been well defined. We evaluated the incidence and predictors of SCD early after AHF hospitalization.

Hypothesis:
AHF is associated with SCD.

Methods:
ASCEND-HF included patients with AHF with any ejection fraction (EF). Clinical events including SCD, resuscitated SCD (RSCD), and sustained ventricular tachycardia/ventricular fibrillation (VT/VF) were adjudicated through 30 days. Patients could have more than one event. These three events were combined to form a new composite endpoint, and baseline characteristics associated with this composite were determined by logistic regression and stepwise selection. RSCD and VT/VF were used as time dependent variables in a Cox model to evaluate the association with 180-day all-cause mortality.

Results:
Among 7,011 patients with available date on SCD, RSCD, or VT/VF, median age was 67 years (IQR 56-76), median EF was 30% (IQR 20-37%), 9% had a history of VT, and 16% had an ICD. The 30-day event rates were 1.8% (n=121) for the composite, 0.6% for SCD (n=43), 0.4% for RSCD (n=24), and 0.9% for VT/VF (n=64). In the multivariable model, chronic obstructive pulmonary disease, history of VT, male sex, higher admission heart rate, and longer baseline QRS duration were associated with SCD, RSCD, or VT/VF (Table). The composite was independently associated with higher 180-day mortality (adjusted HR 6.6, 95% CI 4.8-9.1, p<0.0001).

Conclusions:
Patients admitted for AHF had relatively high rates of SCD, RSCD, or VT/VF within 30 days of follow-up, and RSCD or VT/VF were associated with higher 180-day mortality. Further studies are needed to evaluate ways to predict and therapies to prevent and treat tachyarrhythmias early after AHF hospitalization, including in those patients who may be eligible for an ICD after medical therapy has been optimized.
Abstract 17313: Multiparametric Cardiac MRI Documents Reduced LV Remodeling and Improved Contractile Function in Regions Adjacent to the Infarct After Pharmacologic Immunomodulation via Adenosine 2a Receptor Stimulation
Authors: Cheng Ya-Jian , Chemaly Elie R , Tian Yikui , Epstein Frederick H , French Brent A
Published: July 2021

Introduction:
Agonists of the Adenosine 2a Receptor (A2aR) are used clinically as pharm-stress agents for perfusion imaging, but they are also potent immunomodulators that reduce the size of acute MI when administered at reperfusion in both large and small animal models of MI.

Hypothesis:
Sustained administration of an A2aR agonist can reduce post-MI LV remodeling and improve cardiac strain even when treatment is withheld until after infarct size has stabilized.

Methods:
Two groups of mice were studied: C57BL/6 mice treated with Vehicle or a highly selective A2aR agonist (ATL313). All mice received 1h coronary occlusion and 28d of reperfusion. ATL313 was administered for 28 days by subcutaneous micro-osmotic pumps implanted after MI. All mice underwent 7T CMR imaging at baseline and 2, 7 & 28 days post-MI. CMR included short-axis black-blood cines covering the entire heart, with mid-ventricular cine DENSE for circumferential strain (Ecc). Late Gd-enhanced (LGE) inversion recovery imaging was performed on Days 2&7 and molecular imaging with a collagen-targeted Gd contrast agent (EP3533) on Days 14&28. Mice with Day 2 LGE infarct sizes less than 22% or >42% LV mass were excluded from analysis.

Results:
Examples of LGE and DENSE analysis are shown in Panels A&B. Day 2 infarct size was similar between groups (ATL313 (n=9): 35±2 vs Vehicle (n=8): 34±2, mean±SEM, p=NS). In panel C, ATL313 significantly improved LV end-systolic volume as early as 2 days post-MI (mean±SEM, *p<0.05 vs Vehicle). In panel D, ATL313 improved Day 2 Ecc in adjacent zones vs. Vehicle (-10±2 vs -6±2%, *p<0.05). In panel E, ATL313 reduced LV mass at Day 28 vs Vehicle (121±7 vs 143±7mg, *p<0.05).

Conclusions:
Pharmacologic immunomodulation with an A2aR agonist inhibits LV remodeling, improves contractile function in infarct-adjacent regions at Day 2 post-MI and reduces LV mass at Day 28. Combined with previous work, these results suggest that A2aR stimulation may prove beneficial in both acute and sub-acute MI.
Abstract 17334: The Detrimental Effect of Chest Compression Interruptions on Coronary Perfusion Pressure Dynamics
Authors: Paradis Norman A , Moodie Karen L , Kaufman Christopher L , Lampe Joshua W
Published: July 2021

Introduction:
Guidelines for treatment of cardiac arrest recommend minimizing interruptions in chest compressions based on research indicating that interruptions compromise coronary perfusion pressure (CPP) and blood flow and reducing the likelihood of successful defibrillation. We investigated the dynamics of CPP before, during, and after compression interruptions and how they change over time.

Methods:
CPR was performed on domestic swine (~30 Kg) using standard physiological monitoring. Blood flow was measured in the abdominal aorta (AAo), the inferior vena cava, the right common carotid and external jugular. Ventricular fibrillation (VF) was electrically induced. Mechanical chest compressions (CC) were started after four minutes of VF. CC were delivered at a rate of 100 compressions per minute (cpm) and at a depth of 2” for a total of 12 min. CPP was calculated as the difference between aortic and right atrial pressure at end-diastole per Utstein guidelines. CPP was determined for 5 compressions prior to the interruption, every 2 seconds during the CC interruption, and for 7 compressions after the interruption. Per protocol, 12 interruptions occurred at randomized time points.

Results:
Across 12 minutes of CPR, averaged CPP prior to interruption was significantly greater than the averaged CPP after the interruption (22.4±1.0 vs. 15.5±0.73 mmHg). As CPR continued throughout the 12 minutes, CPP during compressions decreased (First 6 min = 24.1±1.4 vs. Last 6 min = 20.1±1.3 mmHg, p=0.05), but the effect of interruptions remained constant resulting in a 20% drop in CPP for every 2 seconds irrespective of the prior CPP. The increase (slope) of CPP after resumption of compressions was significantly reduced over time (First 6 min = 1.47±0.18 vs. Last 6 min = 0.82±0.13 mmHg/compression).

Conclusions:
Chest compression interruptions have a detrimental effect on coronary perfusion and blood flow. The magnitude of this effect increases over time as a resuscitation effort continues. These data confirm the importance of providing uninterrupted CPR particularly in long duration resuscitations.
Abstract 17352: Predictors of Ventricular Arrhythmias and Sudden Death in a Quebec Cohort With Brugada Syndrome
Authors: Rivard Lena , Roux Antoine , Nault Isabelle , Champagne Jean , Roux Jean-Francois , Talajic Mario , Tadros Rafik , Cadrin-Tourigny Julia , Shohoudi Azadeh , Mondesert Blandine , Roy Denis , Macle Laurent , Andrade Jason , Dyrda Katia , Dubuc Marc , Guerra Peter G , Guerra Peter G , Sarrazin Jean-Francois , Thibault Bernard , Khairy Paul
Published: July 2021

Introduction:
Patients with Brugada syndrome (BrS) are at risk for ventricular arrhythmias (VAs) and sudden death. Identification of high-risk individuals beyond those with syncope or resuscitated SCD remains a major challenge. We sought to assess the value of clinical, electrophysiological, and ECG features of depolarization and repolarization in predicting arrhythmic events and SCD in a Quebec population.

Methods:
Consecutive patients with BrS diagnosed between 2002 and 2013 were recruited from three major university hospitals in the province of Quebec, Canada. Relevant clinical features were recorded at baseline. Qualifying ECGs with the highest type 1 ST-segment elevations were reviewed and analyzed by two electrophysiologists blinded to clinical history, with the following parameters assessed: S duration in V1, aVR sign, QRS duration in V6, R-J interval in V2, maximal Tp-e, duration, Tp-e dispersion, QRS-f, ST elevation and QTc in V2, and presence of an inferolateral ER pattern. Survival analyses considered a left truncation model to account for potential sampling bias, considering that those who died suddenly before recognition of BrS were necessarily excluded.

Results:
A total of 105 consecutive patients, 79.8% male, were diagnosed with BrS at a median age of 48 years and were followed for 5.0±1.2 years. Ten (9.5%) had a history of SCD, 37 (35.2%) had syncope, and 7 (6.7%) experienced 20 arrhythmic events during follow-up (7 anti-tachycardia pacing; 13 shocks). In multivariate Cox regression analyses adjusted for left truncation and Firth bias correction, a spontaneous type I ECG pattern (HR 10.80; 95% CI 1.03 to 113.87; p=0.0476)], maximal Tp-e duration ≥100ms (HR 29.73; 95% CI 1.33 to 666.37; p= 0.0325) and QRS duration in V6>110 ms (HR 15.27; 95% CI 1.07 to 217.42; p=0.0443) were independently associated with VAs or aborted SCD. Family history of SCD, AF, and inducible VAs during programmed ventricular stimulation were not associated with the primary endpoint.

Conclusion:
In a cohort of patients with BrS from the province of Quebec, VAs and SCD were independently associated with standard 12-lead ECG features including a spontaneous type 1 pattern, depolarization (QRS in V6 >110 ms), and repolarization (maximal Tp-e duration) criteria.
Abstract 17385: CPR Education in High-need Schools to Increase Student Knowledge and Comfort Performing CPR
Authors: Heard Debra , Sasson Comilla
Published: July 2021

Introduction:
Low-income neighborhoods are important targets for CPR trainings as they typically have high incidence of out-of-hospital cardiac arrest and low prevalence of bystander CPR. Training middle school students in these neighborhoods is a novel intervention to increase CPR awareness.

Objective:
Conduct a school-based CPR intervention using classroom teachers as facilitators at 1131 middle schools across the United States with a high proportion of students from lower-income families.

Methods:
Population: 1131 public middle and high schools in 34 states (including the District of Columbia) were selected for the 2014-2015 school year to participate based on close proximity to sponsor’s U.S. store locations and 50% or more student eligibility for free or reduced-price lunch. Intervention: Participants completed a pre-test survey to assess baseline knowledge of CPR and comfort performing CPR. A classroom Hands-Only CPR training lasting one class period was conducted with the CPR in Schools Training Kit™, which includes an educational DVD, 10 manikins and resources for any classroom teacher to conduct trainings. Participants then completed post-training knowledge and comfort survey. McNemar’s tests on paired data and chi square and t-tests on aggregated unpaired data were conducted to assess for differences in CPR knowledge and comfort performing CPR pre- and post-training.

Results:
Training data were returned by 563 (49.8%) participating schools training a total of 150,409 students in Hands-Only CPR. Using a sample of returned data, the mean number of questions answered correctly on CPR knowledge increased from 2.5 to 4.2 (out of 5). The majority of participants (75.8%) felt comfortable performing Hands-Only CPR after the intervention.

Conclusion:
A total of 150,409 students from 563 schools were trained in Hands-Only CPR (average 267 students/CPR in Schools Training Kit). At $625 per CPR in Schools Training Kit (with 10 manikins and materials), training cost $4.70 for each student trained. Participants demonstrated increased knowledge of and comfort performing CPR. The CPR in Schools Training Kit is a low cost and promising method for increasing bystander CPR awareness in the student population in low-income neighborhoods.
Abstract 17401: Ranolazine: A Novel Anti-ischemic Drug in Preventing Post-operative Af in Patients Undergoing Coronary Artery Bypasses Grafting: Meta-analysis
Authors: Trivedi Chintan , Di Biase Luigi , Mohanty Sanghamitra , Gianni Carola , Gunes Mahmut , Gökoglan Yalçin , Natale Andrea
Published: July 2021

Introduction:
Atrial fibrillation (AF) is common after coronary artery bypass grafting (CABG). Ranolazine is a novel drug used in the treatment of angina, which also has antiarrhythmic properties. Recent studies demonstrated the benefit of ranolazine in preventing post-operative AF (POAF) in patients undergoing CABG.

Hypothesis:
To assess the role of ranolazine in preventing POAF in patients undergoing CABG surgery.

Methods:
We performed comprehensive search of PubMed, MEDLINE, and Cochrane library database on the study assessing the effectiveness of ranolazine in preventing POAF by comparing it with standard therapy. Meta-analysis was performed by fixed effect model by entering POAF events and the total population from each study. Data are expressed as Odds ratio (OR) with 95% confidence interval (CI).

Results:
A total of three studies with 628 patients (259 pts in ranolazine group, 369 pts in standard therapy group) were included in the meta-analysis. In pooled analysis, ranolazine was associated with 54% reduction in post-operative AF events compared to standard therapy [odds ratio = 0.46 (0.31, 0.70), P<0.001]. The number needed to be treated was 7.14. In one of the study, more patients in ranolazine group (52.2%) had symptomatic hypotension three days after the surgery.

Conclusions:
Ranolazine may prove beneficial in the prevention of POAF following CABG. However, because of small number of studies further research with large randomized clinical trial is warranted to determine specific dose and duration of ranolazine therapy.
Abstract 17413: Influence of Endothelial Function and Rho-Associated Kinase Activity in Patients With Primary Aldosteronism
Authors: Matsumoto Takeshi , Higashi Yukihito , Iwamoto Akimichi , Kajikawa Masato , Oda Nozomu , Maruhashi Tatsuya , Nakashima Ayumu , Noma Kensuke , Kihara Yasuki
Published: July 2021

Background:
Primary aldosteronism (PA) is a most common cause of secondary hypertension and patients are divided into two subtypes in clinically, aldosterone producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). Hypertension is associated with endothelial dysfunction. It is well known that endothelial dysfunction is an independent predictor of cardiovascular events. Rho-associated kinases (ROCKs), one of the first downstream targets of the small GTP-binding protein Rho A, mediate various cellular physiologic functions. It has been reported that an increase in ROCK activity is associated with cardiovascular diseases, including hypertension. However, there is little information on the relationship between subtype of PA and the grade of atherosclerosis. The purpose of this study was to evaluate the vascular function and ROCK activity in patients with PA.

Methods:
Vascular function, including peripheral arterial tonometry (PAT) and ROCK activity in peripheral leukocytes were evaluated in 18 patients with APA group (49.5±15.5 years, 7 males), 14 patients with IHA group (56.1±11.0 years, 8 males), and 23 age-, gender-, and blood pressure-matched EH group (55.6 ± 9.9 years, 13 males).

Results:
PAT ratio was significantly lower in the APA and IHA groups than in the EH group (0.62±0.23 vs. 0.62±0.24 and 0.79±0.28, P<0.05, respectively), whereas there was no significant difference in PAT ratio between the APA group and IHA group. ROCK activity was significantly higher in the APA group than in the IHA group and EH group (1.36±0.58 vs. 0.95±0.51 and 0.80±0.39, P<0.05 and P<0.001, respectively), whereas there was no significant difference in ROCK activity between the IHA group and EH group. PAT ratio correlated with plasma aldosterone concentration (PAC) (r=-0.36, P<0.01) and plasma renin activity ratio (ARR) (r=-0.26, P=0.05). ROCK activity correlated with serum potassium (r=-0.27, P=0.05), PAC (r=0.39, P<0.01) and ARR (r=0.49, P<0.01).

Conclusions:
APA and IHA were associated with endothelial dysfunction and APA increased ROCK activity compared with those in IHA and EH. These findings suggest that APA may have a higher risk of future cardiovascular events.
Abstract 17452: Inter-atrial Conduction Time Can Predict New-onset Atrial Fibrillation After Radiofrequency Ablation of Isolated, Typical Atrial Flutter
Authors: Henmi Ryuta , Ejima Koichiro , Yagishita Daigo , Iwanami Yuji , Shoda Moria , Hagiwara Nobuhisa
Published: July 2021

Introduction:
Previous studies showed inter-atrial conduction delay (IACT) is an important electrophysiological factor predicting atrial fibrillation (AF) after successful atrial flutter (AFL) ablation. To the best of our knowledge, there has no previous study regarding the prognostic value of IACT as a predictor of new-onset AF after AFL ablation without AF history.

Hypothesis:
The purpose of this study was to determine the incidence and predictors of new-onset AF after Radiofrequency ablation (RFA) of isolated AFL in a retrospective cohort study.

Methods:
This study included consecutive patients who underwent successful RFA of isolated, typical AFL from 2004 to 2012. Patients with any history of AF prior to AFL ablation were excluded. IACT was defined as the interval from the onset of P-wave in 12-lead electrocardiogram to atrial intracardiac electrogram at the distal coronary sinus catheter.

Results:
Eighty patients were included in this study. During a mean follow-up 3.4±2.6 years after successful AFL ablation, 22 patients (27.5%) developed new-onset AF. A Cox regression multivariate analysis demonstrated that IACT was the independent predictor of new-onset AF after AFL ablation (odds ratio: 13.3; 95% confidence interval: 1.36-152.5; p=0.0255). IACT was accurate in predicting new-onset AF (AUC=0.70). The optimal cut-off point of IACT for predicting new-onset AF was ≧120ms, with a sensitivity of 0.476 and a specificity of 0.898. Kaplan-Meier curves showed that new-onset AF after AFL ablation was significantly higher in the patients with IACT ≧120ms compared to the patients with IACT< 120ms (p=0.0016).

Conclusions:
IACT is an independent risk factor for new-onset AF after AFL ablation without a history of AF.
Abstract 17454: Inhibition of Anti-angiogenic VEGF-A Isoform Activates a Novel VEGFR1 Signaling That Induces Therapeutic Angiogenesis and Perfusion Recovery in Experimental PAD
Authors: Ganta Vijay C , Kutateladze Anna , Choi Min , Annex Brian
Published: July 2021

Introduction:
Classic VEGF-A induced angiogenesis involves VEGFR2 (VR2)-PI3K-AKT-eNos activation. Ischemia induces VEGF165b (V165b, an anti-angiogenic VEGF-A isoform) levels in Peripheral Arterial Disease (PAD) muscle. Since V165b competes with pro-angiogenic VEGF-A isoforms to bind and block VEGF-A dependent activation of VR2 and angiogenesis, we hypothesized that “V165b inhibition removes the anti-angiogenic brakes on VR2-PI3K-Akt signaling to promote therapeutic angiogenesis and perfusion recovery in PAD”.

Methods and Results:
Hind limb ischemia (HLI), an experimental PAD model was performed by femoral artery ligation and resection in worse recovery animal strains (Balbc and type 2-Diabetes (T2D), n=10/group). Mice were treated i.m. with isoform specific V165b blocking antibody or IgG immediately post-surgery. V165b inhibition significantly increased perfusion recovery (Balbc: V165b-Ab=75.35±4.7 vs. IgG=50.13±2.4%, T2D: 65.70±5.8 vs. 44.04±6.08%) assessed by laser Doppler. Furthermore, V165b inhibition increased vascular density by ~2 fold in ischemic muscle and significantly decreased necrosis scores in both animal strains compared to IgG. In vitro, HUVECs treated with V165b-Ab showed significantly higher capillary like tube formation on matrigel suggesting that endogenous V165b inhibition is sufficient to promote angiogenesis. In stark contrast to our hypothesis, V165b inhibition significantly induced VR1 activation but not VR2, along with Stat3 activation, decreased Akt, Erk1/2 activation and decreased P53 levels (in d3 post HLI tissue samples) compared to IgG. In vitro, HUVECs treated with V165b-Ab also showed significant increase in VR1 and Stat3 activation compared to IgG. Moreover, ligand-receptor binding experiments showed that V165b inhibition significantly increased the binding of not only VEGF-A but also VEGF-B and PlGF to VR1 in ischemic muscle as well as in HUVECs in vitro (P<0.05 is considered significant).

Conclusion:
We conclude that V165b not only competes with VEGF-A but also with VEGF-B and PlGF to bind and block VR1 activation in ischemic muscle. Our data point towards a novel VR1 signaling that activates Stat3 and inhibits P53 to promote perfusion recovery in ischemic muscle post V165b inhibition.
Abstract 17462: Relevance of Regulatory T Cells to Gender Dimorphism in Pulmonary Hypertension
Authors: Tamosiuniene Rasa , Nguyen Linh , Luria Ayala , Sante Joshua , Saito Toshie , Rabinovitch Marlene , Voelkel Norbert , Habtezion Aida , Nicolls Mark
Published: July 2021

Idiopathic Pulmonary Arterial Hypertension (IPAH) is a disease with female predominance. A growing body of evidence shows reciprocal relationship between sex steroids and the immune system. The aim of the present study was to determine whether the absence of Tregs with the presence of endogenous estrogen mediate the development of PH in a gender-specific manner and if protective signaling pathways of Tregs prevent gender dimorphism of PH susceptibility in T cell deficient animal model of PH.

Methods and Results:
in two utilized models of PH inbred Wag T cell deficient athymic (AT) nude male and female rats were given s/c SU5416 in normoxia or treated with chronic hypoxia (CH) for 21d. In IR experiments, AT rats received purified CD4+CD25+hi/Tregs. We also tested the effect of murine/human Tregs or CD4+CD25- on primary rat lung, cardiac and human lung microvascular ECs (RLMECs, HLMECs, RCMECs) with set-up of cocultures.

In both PH models treatment resulted in development of PH with significantly higher RVSP and particular significantly pronounced RVH in female than in male in both SU5416 and CH groups (Fulton index: 0.41±0.01vs.0.33±0.02 and 0.52±0.03vs.0.37±0.01, p< 0.05). However, circulating estrogen levels were found to be significantly elevated in female than in male in all animal groups. For both female and male AT animals IR of Tregs prevented PH with RV remodeling, as well as decreased perivascular fibrosis and increased estrogen receptor (ER)β expression in lung and RV vascular wall.

In vitro studies on coculture of Tregs with RLMECs and RCMECs resulted in an upregulation of IL-10, HO-1, PDL1, ERα, ERβ, activation of pAKT pathway, and endothelial nitric oxide synthase (eNOS), which was abrogated with ER antagonist ICI182,780.

In addition, compared with control male AT rats, control female animals had increased expression of HO1, HO2 enzymes in lung and RV vascular wall endothelial/Reca+ cells as well as increased capillary density in RV. Thus, differential HO expression between the genders might account for the PH susceptibility.

Conclusions:
Our data suggest that Tregs signaling is required as a major mechanism with possible mutual interaction of endogenous estrogen to prevent endothelial injury related gender dimorphism for the development of PH.
Abstract 17537: Stably Expressed APEX2 Identifies the Integration of iPSC-derived Cardiomyocytes in a Mouse Model of Myocardial Infarction
Authors: Hatani Takeshi , Funakoshi Shunsuke , Deerinck Thomas J , Bushong Eric A , Kimura Takeshi , Yamanaka Shinya , Ellisman Mark H , Hoshijima Masahiko , Yoshida Yoshinori
Published: July 2021

Background:
Although studies have feasibility of
in vivo
cardiac transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in animal experiments, nano-structural confirmation of the successful incorporation of the engrafted iPSC-CMs including electron microscopy (EM) has not been accomplished, partly because identification of graft cells in EM has proven to be difficult. However, with a new genetically encoded probe, the monomeric 28-kDa peroxidase reporter 2 (APEX2), which withstands strong EM fixation, this problem can now be done. We have now been able to test whether APEX2 can identify iPSC-CMs in host heart after long-term engrafting, and evaluate the engrafted iPSC-CMs in post-myocardial infarction using EM.

Methods:
We established human iPSC lines which stably expressed histone H2B-APEX2 (APEX2 iPSCs). After differentiating APEX2 iPSCs into CM in vitro, purified cells were transplanted into NOG mouse hearts with myocardial infarction by direct injections into the myocardium. One and 3 months after transplantation, we mapped engraft iPS-CMs using high resolution micro-CT and evaluated their ultrastructure by EM.

Results:
APEX2 was stably expressed and labeled histone H2B in iPSCs before and after
in vitro
differentiation into CM. Graft efficiency of APEX2 iPSC-CMs in NOG heart was excellent and APEX2 expression sustained over 3 months
in vivo
. APEX2 reaction observed in EM clearly identified engrafted APEX2 iPSC-CMs in niches surrounded by host CMs and their physical interaction was visualized. EM also revealed a progression in the maturation of sarcomeric structure and mitochondria in engrafted iPSC-CMs, by comparing data at 1 and 3 months after transplantation.

Conclusion:
We demonstrate that APEX2 is a versatile genetic reporter to trace cell fates in living animals over many months. Using APEX2-based staining, we were able to identify and characterize the maturation process of iPSC-CMs, and determine how they distribute within myocardial niches, as well as their interaction with host CMs. This method should be useful to many studies of stem cell-based cell replacement therapy, as it allows both tracking of cells and the ultrastructural characterization of engrafted cell and graft-host interactions.