bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18740: Influence of Oral Progesterone Administration on QT Interval Response to Ikr Inhibition
Authors: Tisdale James E , Jaynes Heather A , Overholser Brian R , Sowinski Kevin M , Flockhart David A , Kovacs Richard J
Published: July 2021

Introduction:
Evidence from pre-clinical and human studies suggests that higher serum progesterone concentrations may be protective against drug-induced QT interval lengthening.

Hypothesis:
Oral progesterone administration attenuates QT interval response to I
Kr
inhibition.

Methods:
In this prospective, double-blind, crossover study, 15 healthy female volunteers ages 21-40 years were randomized to receive progesterone 400 mg or matching placebo orally once daily for 7 days timed to the menses phase of the menstrual cycle (between-phase washout period = 52 days). On day 7, a low dose of ibutilide (0.003 mg/kg) was infused over 10 minutes, after which QT intervals were recorded and blood samples serially collected for 12 hours post-infusion. Prior to the treatment phases, subjects underwent ECG monitoring for 12 hours to calculate individualized heart rate-corrected QT intervals (QT
c
I).

Results:
There was no significant difference in maximum serum ibutilide concentrations between the progesterone and placebo phases. (1291±910 vs 1328±718 pg/mL, p=0.87). ECG data are reported from lead II; results are similar from leads V
1
and V
5
. There was no significant difference in pre-ibutilide QT
c
I between the progesterone and placebo phases (Table). Maximum ibutilide-associated QT
c
I, maximum % change in QT
c
I, and % change in area under the effect (QT
c
I) curve during the first hour following ibutilide administration (AUEC
0-1
, s-hr) were significantly lower during the progesterone phase. Progesterone-associated adverse effects were mild, predominantly fatigue/general malaise. Ibutilide-associated adverse effects during the progesterone and placebo phases included bradycardia [3/15 (20%) vs 2/15 (13%)], burning at infusion site [1/15 (7%) vs 1/15 (7%)], and transient (< 1 minute) Bazett’s-corrected QT
c
> 500 ms [0/15 vs 1/15 (7%).

Conclusions:
Oral progesterone administration attenuates QT
c
I lengthening associated with I
Kr
inhibition
Abstract 18745: Major Adverse Cardiac Events After Non-cardiac Surgery Following Previous Percutaneous Coronary Intervention With Stent Implantation
Authors: Wasowicz Marcin , Syed Summer , Starzyk Lukasz , Wijeysundera Duminda , Beattie Scott W
Published: July 2021

Introduction:
It is estimated that 5-16%

of patients (pts) previously treated with percutaneous coronary interventions (PCI) and stent implantation will present for elective non-cardiac surgery (NCS) within 1 year. Despite ACC/AHA recommendations on antiplatelet therapy (ATP) the incidence of perioperative major cardiovascular events (MACE) is high. The objective of this multi-center prospective, cohort study was to determine if APT continued throughout perioperative period decreases the incidence of MI in this population and to determine the mechanism of MACE in post-PCI pts undergoing NCS.

Hypothesis:
There is an association between inadequate platelet inhibition and the incidence of MACE in pts undergoing NCS after previous PCI.

Method:
After REB approval pts after previous PCI scheduled for elective NCS were recruited. The primary outcome was Major Adverse Cardiac Event (defined as MI, stent thrombosis, need for revascularization or 30 day mortality). The incidence of MI was blindly adjudicated in duplicate using the 3
rd
Univ. definition of MI.

Troponin levels were measured every 8h for 2 days, then once daily until discharge in addition to ECG measurements. All pts patient was followed up for any clinical symptoms of MI. The location of MI was also judged based on its location (area of stent or not). The platelet inhibition by aspirin (ASA) and/or clopidogrel was measured using the Platelet Mapping Assay (PMA) performed preoperatively, 1h and 24h after surgery.

Results:
A total of 201 pts were recruited. The incidence of MACE was 21%. Additionally, 11 pts (5%) had isolated troponin elevation. The location of the MI occurred frequently in the area of the stent placement (71%). Pts. exposed to ASA with 5 days of surgery had better platelet inhibition than pts no exposed. There was no difference in platelet inhibition between pts suffering from MI and those who did not. Several factors were associated with increased MACE. These included higher Revised Cardiac Risk Index and pre- and post-operative anemia. 30 patients (15%) suffered from major bleeding complications.

Conclusions:
Results of this study indicated that use of ASA, or its withdrawal, was not associated with MACE in post PCI patients undergoing NCS.
Abstract 18782: Regional Action Potential Heterogeneity in the Murine Pitx2c Deficient Left Atrium
Authors: Holmes Andrew P , Yu Ting , Syeda Fahima , Brown Nigel A , Fabritz Larissa , Kirchhof Paulus
Published: July 2021

Introduction and hypothesis:
Genetic abnormalities close to the Pitx2 gene correlate more strongly with atrial fibrillation (AF) than any other genetic modification. It is known that Pitx2c mRNA is expressed in the adult left atrium (LA), but its relevance for the electrical integrity of cardiomyocytes throughout the atria remains unresolved. We therefore compared regional action potential (AP) morphology in PITX2c
+/-
and wild type (WT) littermate mice.

Methods:
Transmembrane (T) and optical (O) APs were recorded from superfused intact, isolated LA paced at 100ms. TAPs were recorded from three distinct regions on the LA epicardium: 1) the junction with the interatrial septum (S), 2) the medial muscular dome (M) and 3) the lateral wall (L). OAPs were recorded using a custom murine atrial optical mapping system using the Hamamatsu ORCA flash 4 and Di-4-Anepps.

Results:
OAPs were shorter in Pitx2c deficient LA (AP duration (APD70); WT 13±2ms, n=4 LA vs Pitx2c
+/-
9±1ms, n=4 LA, all data as mean±SEM, p<0.05). Simultaneous recordings of OAPs from multiple LA regions showed an AP gradient with longer OAPs at the septum than at the lateral wall, in both genotypes. In WT LA, TAPs were longer and of greater amplitude at the septum than in the other two regions (APD90; S 26±1ms, M 19±1mV and L 19±1ms, APA; S 81±1mV, M 76±2mV and L 76±2mV, n=6 LA, p<0.05). In Pitx2c
+/-
, TAPs were shorter than WT in all three regions tested and exhibited the same regional patterning (S 20±1ms, M 15±1ms and L 16±1, n=7 LA, p<0.05). The regional AP amplitude gradient was not apparent, or at least shifted more towards the lateral wall, in PITX2c
+/-
atria (APA; S 77±2mV, M 76±3mV and L 74±2mV, n=7 LA, ns).

Conclusion:
Partial depletion in Pitx2c mRNA expression causes a uniform APD shortening throughout the LA and loss of regional changes in AP amplitude. Identification of the targets downstream of Pitx2 accounting for these changes will help to better understand the mechanisms conveying AF due to reduced Pitx2 function.
Abstract 18816: Relationship of Aortic Valve Surgery and Survival in Patients with Moderate or Severe Aortic Stenosis and Left Ventricular Dysfunction
Authors: Samad Zainab , Vora Amit N , Dunning Allison , Sivak Joseph A , Shaw Linda K , Vavalle John P , Sherwood Matthew W , Hofmann Paul , Glower Donald D , Kisslo Joseph A , Harrison J. Kevin , Velazquez Eric J
Published: July 2021

Introduction:
Aortic valve replacement (AVR) for aortic stenosis (AS) carries additional surgical risk in patients with left ventricular dysfunction (LVD) but has been associated with survival benefit. The current use of AVR and its relationship to mortality in patients with moderate or severe AS and LVD is ill defined.

Hypothesis:
We hypothesized that AVR was underutilized among patients with moderate/severe AS and LVD, and that it was associated with lower mortality.

Methods:
We queried the Duke Echocardiographic Database for patients with moderate (mean gradient >25 mmHg and/or peak velocity >3m/s) or severe AS (mean gradient >40 mmHg and or peak velocity >4m/s) and LVD (left ventricular ejection fraction [LVEF] <50%) from 1/1/1995-5/1/2014. We used multivariable Cox modeling to assess the relationship of AVR and all-cause mortality.

Results:
We identified a total of 1,634/132,804 patients with moderate (1,095, 67%) or severe (539, 33%) AS and LVD. Severe LVD (LVEF ≤35%) was present in 35% of the cohort. The median age of the cohort was 75 (IQR 67-83), and patients with moderate AS were more likely than those with severe AS to have a history of ischemic heart disease, diabetes, peripheral vascular disease, cerebrovascular disease, and renal disease (all p <0.01). Median logistic EuroSCORE was 9.8 (5.5, 16.8).

Median follow-up time was 1.2 years (IQR 0.2- 3.9). There were 863 deaths in the cohort. Overall, 287 (26%) patients with moderate AS and 263 (48%) patients with severe AS underwent AVR within 5 years of the qualifying echo. After multivariable adjustment, AVR with (n=270) or without CABG (n=280), compared to medical therapy was associated with lower mortality (HR=0.47 [0.38, 0.59], p<0.0001) in the entire cohort. Compared to CABG alone, the combination of CABG + AVR (HR=0.19 [0.14, 0.27], p<0.0001) was associated with a significant survival advantage.

Conclusions:
Among patients with significant AS and LVD, AVR with or without CABG is associated with significant mortality benefit and may be underutilized in this population. Further research is required to understand factors contributing to current practice patterns and the possible utility of transcatheter approaches in this high-risk cohort.
Abstract 18848: Weight Gain is Not a Significant Predictor of Coronary Artery Disease Severity
Authors: Franzese Christopher J , Bliden Kevin P , Gesheff Tania B , Barbour Cescelle B , Gesheff Martin G , Toth Peter P , Tantry Udaya , Gurbel Paul A
Published: July 2021

Background:
Obesity, along with hypertension and diabetes, is a known risk factor for coronary artery disease (CAD). Recent studies have proposed that obese individuals may actually experience less adverse cardiovascular outcomes and mortality compared to non-obese individuals, a phenomenon known as the “obesity paradox”. We sought to determine if weight gain is associated with overall CAD severity measured by coronary angiography.

Methods:
Suspected CAD patients (n=418) were enrolled in the Multi-Analyte, Thrombogenic, and Genetic Markers of Atherosclerosis (MAGMA) study prior to elective cardiac catheterization. Demographics and weight information were obtained, and maximum weight gain (MWG) was defined as the percent increase in weight from year of high school graduation to year of heaviest weight. Subjects were divided into the following quartiles based on MWG: none (≤30%), minor (31%-47%), major (48%-69%), and extreme (≥70%). Detailed lipid profiling was determined by vertical density gradient ultracentrifugation, thrombin-induced platelet fibrin clot strength (TIP-FCS) by thromboelastography, and urinary 11-dehydrothromboxane B2 (11-dhTxB2) by ELISA. Severity of CAD was defined as none/minimal (<20%), moderate (20-75%), and severe (75%) luminal diameter obstruction of any major coronary vessel.

Results:
The average MWG in the study population was 53 ± 33%. Patients in the extreme MWG group had the highest incidence of DM (47.5%), hypertension (80.8%), and depression (25.3%), and were most often female (59.6%). There was an inverse relationship between MWG and CAD severity (p=0.005)(figure). TIP-FCS increased in a stepwise fashion with MWG (p=0.001). 11-dTxB2 and triglyceride levels were significantly higher in the extreme MWG group, regardless of cholesterol lowering therapy (p<0.05 for all).

Conclusion:
Our data suggest that weight gain is associated with heightened thrombotic risk but not an increased risk for CAD.
Abstract 18870: Adjudicated versus “Administrative” Heart Failure With Preserved Ejection Fraction
Authors: Kalogeropoulos Andreas P , Patel Akash , Li Song , Burkman Gregory , Papadimitriou Lampros , Zhang Lane , Lebeis Taylor A , Farooq Kanwal , Georgiopoulou Vasiliki V , Butler Javed
Published: July 2021

Introduction:
The proportion of heart failure (HF) with preserved ejection fraction (HFpEF) is reported to be as high as 40%-60% based on administrative data, but these estimates have not been clinically validated.

Methods:
We evaluated 1752 consecutive patients who received outpatient care during the first quarter of 2012 for an encounter ICD-9 code of 402.X1, 404.X1, 404.X3, or 428.XX. Medical records were reviewed for HF symptoms, signs, and treatment; last reported ejection fraction (EF); all previous EF documentations; and special causes of HF (congenital heart disease or specific cardiomyopathies). We classified confirmed HF cases not due to special causes into 3 mutually exclusive categories: (1) HFpEF: current EF >40% without any previous EF ≤40%; (2) HF with recovered EF (HFrecEF): current EF >40% but previous EF ≤40%; and (3) HF with reduced EF (HFrEF): current EF ≤40%.

Results:
HF was confirmed in 1652 cases (94.3%). Among these, 321 had HFpEF (19.4%; 95%CI 17.6-21.4); 268 had HFrecEF (16.2%; 95%CI 14.5-18.1); and 992 had HFrEF (60.0%; 95%CI 57.7-62.4); the remaining 71 cases (4.3%) had HF due to special causes. In comparison, the proportion of HFpEF on the basis of ICD codes and last EF without further adjudication would have been 39.0%. Patient characteristics are summarized in
Table 1.
After 2 years of follow up, age- and gender- adjusted mortality was 10.2% in HFrEF, 8.6% in HFpEF, and 4.4% in HFrecEF patients (stratified log-rank P=0.005),
Fig. 1
.

Conclusions:
The proportion of clinically verified HFpEF is considerably lower compared to estimates from administrative data. Many patients with preserved EF actually represent HFrecEF, which has a more favorable prognosis.
Abstract 18881: New Oral Anticoagulants for Periprocedural Management of Anticoagulation in Patients Undergoing Radiofrequency Catheter Ablation for Atrial Fibrillation: a Meta-analysis
Authors: Parwani Abdul Shokor , Blaschke Daniel , Wutzler Alexander , Huemer Martin , Attanasio Phillip , Boldt Leif-Hendrik , Haverkamp Wilhelm
Published: July 2021

Introduction:
Thromboembolic events are the most feared complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). The traditional periprocedural anticoagulation approach is discontinuation of vitamin K antagonist and bridging with heparin. Newly procedures are done under therapeutic INR 2-3. Recent studies used periprocedural new direct oral anticoagulants (NOACs).

Hypothesis:
We evaluated the available evidence on the efficacy and safety of NOACs for periprocedural anticoagulation during RFCA of AF.

Methods:
Pubmed, Embase and Cochrane Central were searched. Retrospective and prospective studies published as peer-reviewed full-size articles were included if they reported embolic events and major and minor bleeding.

Results:
Fifteen studies were identified (14 observational studies, 1 small randomized trial). A total of 7050 patients were included (NOACs group: 2887 ). A total of 37 thromboembolic complications occurred (0,5%) with 17 events in the NOAC group (0,6%) and 20 in the warfarin group (0,5%) (odds ratio 0.97, 95% confidence interval (CI) 0.48 to 1.99). Major bleeding were numerically higher in the warfarin group compared to the NOACs group. However, the difference did not reach statistical significance (odds ratio 0.69, CI 0.43 to 1.10). Subgroup analysis did not reveal any differences in event rates.

Conclusions:
Our review suggests that dabigatran etexilate and rivaroxaban are as effective and safe as warfarin for periprocedural anticoagulation in patients undergoing RFCA of AF. However, it has to be acknowledged that the current evidence is mainly based on observational studies.
Abstract 18929: Pacing in the Adult Fontan Patient: Risky Business?
Authors: Lewis Matthew J , Colaco Nalini , Ginns Jonathan , Rosenbaum Marlon
Published: July 2021

Introduction:
Chronic ventricular pacing can induce a cardiomyopathy in patients with a biventricular heart; however, the effect of chronic pacing in adult patients with a Fontan has not been well characterized. We hypothesized that paced adult Fontan patients would be at higher risk for death or heart transplant.

Methods:
We performed a retrospective, cohort of study of all adult Fontan patients at the Schneeweiss Adult Congenital Heart Center seen between 1/1997 and 5/2014. Two Cohorts were defined based on whether a patient did or did not have a permanent pacemaker. Demographic and clinical characteristics were collected via chart review. The primary endpoint was a composite of death or heart transplant.

Results:
Of the 98 adult Fontan patients followed (mean age at last follow-up 32± 8 years), 30 (31%) had a pacemaker. Pacemaker specific data was available on 25 of the 30 (83%) paced patients. Of those, 88% were paced >50% of the time. Patient diagnoses included double inlet left ventricle in 33 (34%), tricuspid atresia in 26 (27%), hypoplastic left heart in 9 (9%), heterotaxy in 8 (8%), and 22 (22%) with other diagnoses. Fifty-two patients (53%) had a classic RA-PA Fontan and 46 (47%) had a lateral tunnel or extracardiac Fontan.

Over the study period, 16 patients met the primary endpoint and 12 (75%) were paced. Paced patients were significantly more likely to have worse functional status (p<0.001), be on diuretics (p<0.001), and have a higher mean creatinine (P=0.025), mean total bilirubin (p=0.025), and mean Fontan pressure (p<0.001). Pacing was associated with >4-fold increase in the rate of death or heart transplant (p=0.009) in a multivariate cox-proportional hazard model that included Fontan type, age at Fontan completion, age at follow-up, and pacing status.

Discussion:
In our cohort of 98 adult Fontan patients, paced patients were more likely to have worse functional status, require diuretics and had a >4-fold increased risk of death or heart transplant. These results suggest that chronic pacing may be detrimental in this population.
Abstract 18942: Is Bilirubin Protective Against Anthracycline-induced Cardiomyopathy?
Authors: Vera Trinity , Morgan Timothy M , Jordan Jennifer H , Whitlock Matthew C , Kitzman Dalane , Hundley W. G
Published: July 2021

Introduction:
Reductions in left ventricular ejection fraction (LVEF) may occur after the administration of anthracycline-based chemotherapeutic regimens. Oxidative stress at the myocellular level has been implicated in these reductions, and as a consequence, we hypothesized that bilirubin, an effective endogenous anti-oxidant, would ameliorate some of the reductions in LVEF associated with anthracyline administration.

Methods:
From 1/1/2002 to 12/31/2012, we identified 751 consecutive individuals who were treated with anthracyclines at Wake Forest Baptist Medical Center, received serial LVEF measures, and exhibited basal serum bilirubin levels < 2mg/dl prior to their treatment for cancer. The correlation between pre-chemotherapy bilirubin levels and serial pre- to post-chemotherapy changes in LVEF was analyzed using linear regression models. For dose response analysis, the participants were divided into 3 groups based on their bilirubin levels. ANOVA was used to test for the difference in the mean LVEF change across groups. Tukey’s Studentized Range test was used in pairwise comparisons. Chi-square test was used for categorical variables.

Results:
There were 65 (35%), 86 (30%) and 68 (24%) participants whose LVEF decreased by more than 15% in Group 1 (bilirubin ≤0.5mg/dl), Group2 (bilirubin 0.6 - 0.8mg/dl) and Group 3 (bilirubin 0.9 - 1.9mg/dl) respectively (Table 1). On pairwise comparison, there was a significant decrease in LVEF between Group 1 and Group 3 (2.9, 95% CI: 0.15 - 5.7). After adjusting for age, BMI, race, CAD/MI, diabetes, hematocrit and medications; increased bilirubin and reduced BMI were associated with LVEF preservation (p = 0.028 and 0.033 respectively).

Conclusions:
In patients treated with anthracyclines, bilirubin level was negatively correlated with reduction in LVEF. These results have potential therapeutic implications for preserving left ventricular function in patients treated with anthracyclines.
Abstract 18945: Baseline Myocardium At-Risk Predicts Subsequent Myocardial Injury in Non ST-Segment Elevation Acute Coronary Syndrome
Authors: Chang Henry , Dickerson Jennifer A , Verhaert David , Simonetti Orlando P , Ambrosio Giuseppe , Crouser Elliott D , Raman Subha V
Published: July 2021

BACKGROUND:
Increased myocardial injury visualized by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) portends worse outcomes in patients with acute coronary syndromes (ACS). Although non ST-segment acute coronary syndromes (NSTE-ACS) comprise 70% of all ACS and 1-year mortality rates are similar to the more readily-diagnosed and uniformly-treated ST-elevation myocardial infarction, ischemic changes and treatment strategies in NSTE-ACS are not well-defined, Studies have shown that T2-weighted (T2W) cardiac magnetic resonance (CMR) may be a marker of acute myocardial injury in ACS. We hypothesized that the presence of at-risk myocardium, identified by T2W CMR at presentation, predicts increased subsequent myocardial injury by LGE beyond traditional risk predictors in NSTE-ACS.

METHODS & RESULTS:
48 patients enrolled in a prospective study of NSTE-ACS underwent CMR with short tau inversion recovery (T2W STIR) imaging and LGE prior to intervention and repeat CMR 61 ± 27 days later. Baseline presence/absence of increased myocardial signal intensity by T2W STIR was determined by consensus of two expert reviewers blinded to other data. In 13 patients (27%), follow-up LGE images showed more extensive injury compared to baseline. Peak troponin at time of event, baseline TIMI risk score and baseline LGE score did not predict subsequent LGE score increase (p=0.13, p=0.48, p=0.55, respectively). Conversely, a much higher proportion of patients with vs. without increased T2W STIR SI at baseline demonstrated increased myocardial injury by LGE at follow-up (12/31 vs. 1/17, p<0.01; Figure).

CONCLUSION:
Myocardium at-risk by T2-weighted STIR CMR in patients with NSTE-ACS predicts subsequent myocardial injury, more so than clinical predictors or extent of baseline myocardial damage. Prospective studies that intensify care for patients with at-risk myocardium may help identify strategies to improve myocardial salvage and reduce mortality in NSTE-ACS.
Abstract 19: Fibrinogen Gamma-Chain Peptide-Coated, Adenosine Diphosphate-Encapsulated Liposomes Rescue Lethal Blast Lung Injury Hemorrhage via Purinergic Signaling
Authors: Hagisawa Kohsuke , Miyawaki Hiroki , Kinoshita Manabu
Published: July 2021

Background:
Fibrinogen gamma-chain (HHLGGAKQAGDV, H12)-coated, adenosine-diphosphate (ADP)-encapsulated liposomes [H12-(ADP)-liposomes] that accumulate at bleeding sites via interaction with activated platelets via GPIIb/IIIa and release ADP.

Objective:
To elucidate the effect of H12-ADP-liposomes and its mechanisms on the lethal pulmonary hemorrhage following blast injury.

Methods:
Mice were pretreated with H12-ADP-liposomes (n=14), ADP-liposomes (n=10), PBS-liposomes (n=10) or normal saline (n=14). A single shot of laser induced shock wave (LISW, 1.8 J/cm2) caused lethal diffuse alveolar hemorrhage in mice. Furthermore, to examine the adenosine effect of H12-ADP-liposomes, adenosine A2A receptor antagonist (ZM241385, n=6) or adenosine A2B receptor antagonist (PSB 1115, n=6) was administered 1 hr before the H12-ADP-liposomes + LISW procedures. Among them, the acute prognosis (survival rates) and pathological injury score (blending area) were compared. The levels of albumin and MIP-2 in the bronchoalveloral lavage fluid (BALF) were measured after LISW in each group.

Results:
H12-ADP-liposomes significantly improved mouse survival (Figure) and reduced the pathological injury score than normal saline (35 vs 40, p=0.004, n=5). H12-ADP-liposomes reduced the albumin leakage (0.8 vs 1.3 mg/ml, p=0.03, n=6) and MIP-2 levels in the BALF (74 vs 355 pg/ml, p<0.01, n=6) than normal saline. Adenosine receptor (especially A2B) antagonists prevented from rescuing and reducing the BALF albumin and MIP-2 leakage by the H12-ADP-liposomes treatment.

Conclusions:
H12-ADP-liposomes may be effective for acute blast lung injury, functioning hemostasis and organ protection via anti-inflammatory purinergic signaling.
Abstract 19040: Exome Sequencing of Extreme Phenotypes Identifies B4GALT2 as a Determinant of Clopidogrel Response Variability
Authors: Scott Stuart , Collet Jean-Philippe , Peter Inga , Yang Yao , Hajjar Roger , Montalescot Gilles , Hulot Jean-Sebastien
Published: July 2021

There is wide interindividual variability in platelet aggregation in response to clopidogrel and high/low on-treatment platelet reactivity (HPR/LPR) is associated with more frequent adverse cardiovascular events. The
CYP2C19*2
allele is the major genetic determinant of clopidogrel responsiveness but only accounts for ~12% of the variation thus urging for identification of additional variants. In a cohort of 636 coronary artery disease (CAD) patients, those with the most extreme pharmacodynamic response to clopidogrel were identified as LPR (P2Y12 reaction units (PRU)<50 and ADP-induced residual platelet aggregation (RPA)<5%) vs HPR (PRU>235 and RPA>60%). Four patients from each group with wild-type
CYP2C19
(
*1/*1)
were subjected to exome sequencing (average 70X). Identified variants that clustered in the LPR or HPR groups (3 or 4 carriers vs. 0) were identified and the probabilities of observing the clustering of each variant according to reported European minor allele frequencies (MAF) were calculated. Forty-nine of the identified variants with the lowest probablilities (18 LPR, 31 HPR, p<0.001) were genotyped across the remaining 628 coronary patients, which identified a significant association between two
B4GALT2
variants (c.909C>T; p.Ile303= and c.366G>C; p.Gln122His, D’=0.68, r
2
=0.30) and treatment response. Carriers of c.909C>T (MAF=0.102) had lower PRU (p=0.0077) and RPA (p=0.0008) compared to non-carriers, as did carriers of c.366G>C (MAF=0.070) with lower PRU (p=0.0211) and RPA (p=0.0046). Notably, these effects were independent of
CYP2C19*2
, suggesting an alternative biological pathway from clopidogrel metabolism. B4GALT2 is a platelet galactosyltransferase that catalyzes the biosynthesis of glycoconjugates and is involved in intercellular recognition and/or adhesion. Taken together, these data implicate
B4GALT2
c.909C>T and c.366G>C as genetic determinants of clopidogrel sensitivity by directly influencing platelet aggregation. Their impact on clinical outcomes of CAD patients deserves further investigation.
Abstract 19106: Diabetes Induced Actin S-glutathiolation Increases Vein Graft Accelerated Atherosclerosis Through Delayed Endothelial Regeneration
Authors: Qi Wei , Krishnan Prakash , Tarricone Arthur , Waqas Ahsan , Zalewski Adrian , Sia Tiffany , Singh Gopal , Wiley Jose , Mehran Roxana , George Isaac , Ali Ayyaz A , Leon Martin B , Ali Ziad A
Published: July 2021

Endothelial cell (EC) loss and regeneration are important aspects of the response to vascular injury leading to atherosclerosis in vein grafts (VG). EC regeneration is known to be impaired in diabetes mellitus (DM) leading to an accelerated atherosclerosis, however the mechanism remains unclear. Given the increased oxidative stress in DM, we hypothesized that protein s-glutathiolation, the reversible covalent addition of glutathione to cysteine on target proteins was a candidate mechanism. Overall s-glutathiolation of proteins measured by immunoblot was significantly increased in human DM atherosclerotic plaque compared to non-DM (4-fold, P<0.01; n =10) with the increase in protein intensity at ≈ 40kDa. Mass spectrometry peptide fingerprint screening identified actin (42Kda) and the actin regulatory protein annexin A2 (39Kda) as the s-glutathiolated proteins. In cultured ECs in which s-glutathiolation was induced, proliferation (22%, P<0.05) and motility (37%, P<0.05) were significantly decreased compared to control. Assessment of actin conformational state identified a significant decrease in the ratio of filamentous to globular actin (P<0.05) supporting our findings of decreased motility. As an in vivo model of acute vascular injury we constructed VGs in apolipoprotein-E knockout (ApoE-KO) mice with expression of an EC reporter gene (LacZ) in which DM was induced by streptoztocin (n=6-10/group). In VGs harvested 28 days post-operatively, DM increased VG total vessel wall area by 51% (P=0.001) and reduced endothelialization by 44% (P=0.001). S-glutathiolation levels were increased 10-fold in primary cultured ECs from these mice. Although there was no differences in baseline EC content or number of isolated cells, following 3 days of culture, total EC number, colony size and colony number from ApoE-KO/LacZ DM mice were decreased (4-fold P=0.05; 3-fold P=0.02; 3-fold P=0.04 respectively, n=6) as were putative EC progenitor levels from bone-marrow derived mononuclear cells by culture (20%,P=0.03) and FACS (22%, P=0.02). These observations indicate an important role for actin s-glutathiolation in EC regeneration following vascular injury and identify a mechanism by which accelerated atherosclerosis develops in patients with DM.
Abstract 19118: Symptom Predictors of Delayed ST-Elevation Myocardial Infarction Presentation
Authors: Hari Pawan , Shenoy Maithili , Doctorian Tanya , Choe David , Desai Amar , Sufficool Daniel , Khan Brian , Pham Minh-Tri , Shadix Steven , Hambik Tankazyan , Tavengwa Hwinei , Liset Stoletniy , Hilliard Anthony
Published: July 2021

Introduction:
Through various systematic initiatives, cardiac centers routinely reach targeted door-to-balloon (DTB) treatment times of less than 90 minutes resulting in improved outcomes. However, in an effort to further optimize outcomes, by reducing total ischemic time, focus on symptom onset and their impact on presentation is needed.

Hypothesis:
This study aimed to identify whether the type and nature of specific symptoms are associated with delays in presentation in STEMI patients.

Methods:
549 patients with complete data presenting with STEMI from April 2008 to December 2012 to a tertiary hospital were retrospectively studied. False activations were excluded. 449 patients were included in this analysis. Symptom-onset-to-hospital arrival time (symptom-onset time was identified by review of medical records, pre-hospital emergency services data and by interviewing patient’s and their family) was analyzed for the following factors: type of symptoms (chest pain, dyspnea, cardiac arrest) and nature of symptoms (constant or intermittent). Non-parametric univariate and multivariate analyses (PROC GLIMMIX) were carried out using Statistical Analysis Systems version 9.1 (SAS Institute, Cary, NC) statistical software package.

Results:
See table

Conclusion:
As expected, STEMI patients presenting with cardiac arrest who survived pre-hospital resuscitation presented the fastest, while patients with dyspnea had a significantly longer delay than patients with chest pain. Patients with intermittent symptoms presented significantly later than those with constant symptoms. Of particular interest, symptom-onset-to-door presentation remains long even with the classical symptom of constant chest pain (the most common STEMI symptom presentation). Thus, continued and enhanced population education and awareness is necessary to see further significant decreases in total ischemic time in STEMI patients.
Abstract 19119: Concomitant Use of Antiplatelet Therapy with Edoxaban or Warfarin in Patients with Atrial Fibrillation in the ENGAGE AF-TIMI 48 Trial
Authors: Xu Haiyan , Ruff Christian T , Giugliano Robert P , Murphy Sabina A , Patel Indravadan , Shi Minggao , Mercuri Michele , Antman Elliott M , Braunwald Eugene
Published: July 2021

BACKGROUND:
Patients with atrial fibrillation (AF) who receive both antiplatelet (AP) and anticoagulant therapy are at markedly higher risk of bleeding. The ENGAGE AF-TIMI 48 trial showed that both the high- (HD) and low-dose (LD) regimens of the once-daily factor Xa inhibitor edoxaban (Edox) were as effective as well-managed warfarin (Warf) (median TTR 68.4%) in preventing stroke or systemic embolism (SEE) with significant reductions in major bleeding and cardiovascular mortality. In this study, we assessed the relative efficacy and safety of Edox as compared with Warf in patients with and without concomitant use of AP therapy.

METHODS:
This was a randomized, double-blind, double-dummy trial comparing HD (60 mg daily, reduced to 30mg in patients with anticipated increased drug exposure) and LD (30 mg daily, reduced to 15mg) Edox with Warf. Dual AP therapy was prohibited while receiving study drug. Cox proportional hazards models were performed stratified by AP use at 3 months with treatment as a covariate.

RESULTS:
Of the 21,105 patients, 4,912 (23%) were receiving AP therapy at 3 months (92% aspirin). Patients who received concomitant AP therapy had higher rates of major bleeding compared to patients who did not (Fig). Both Edox regimens had similar relative efficacy in preventing stroke or SEE compared with Warf regardless of concomitant AP use (P
int
>0.10 for both) with consistent reductions in major bleeding (HD Edox vs. Warf: P
int
=0.91; LD Edox vs. Warf: P
int
=0.59). In patients randomized to LD Edox, AP therapy was associated with a further reduction in the net clinical outcome of death, stroke, SEE, or major bleeding (P
int
=0.02) compared with Warf.

CONCLUSIONS:
Regardless of concomitant AP therapy, both doses of Edox significantly reduced bleeding compared to well-managed Warf. The safety profile of Edox may be particularly attractive in patients with AF who receive a combination of AP and anticoagulant therapy because of higher absolute risk of bleeding.
Abstract 19129: Does System Modification “Really” Modify Survival in Patients With High Defibrillation Threshold? Probably Not
Authors: Siddiqi Najmul , Ahmed Salim , Bhojwani Rohan , Kanj Mohammed , Tchou Patrick , Varma Niraj
Published: July 2021

Introduction:
Defibrillation threshold (DFT) testing is a routine part of implantable cardiac defibrillator (ICD) placement at most centers. If a patient is found to have a high DFT, many physicians perform system modification by adding subcutaneous or transvenous shocking coil to the ICD in an attempt to lower DFT. It is not clear how patients with system modification fare compared to patients without such modification.

Hypothesis:
System modification should have an effect of reducing mortality in patients high DFT when compared with those who don’t undergo it.

Methods:
We retrospectively reviewed demographic and procedural data from 6520 patients who underwent ICD implant at the Cleveland Clinic, between August 1996 and November 2010. The Social Security Death Index was queried to obtain mortality data. High DFT was defined as DFT greater than 25 joules. Among patients with high DFT, survival was compared between those who underwent system modification versus those who did not, using the log-rank test.

Results:
191 patients had a high DFT (mean DFT 30.6+/- 3.4J). The types of ICDs were single chamber 64 (33.5%); dual chamber 72 (37.7%) and cardiac resynchronization or CRT-D 55 (28.8%). 120 patients underwent a system modification (mean DFT after modification was 24.3+/- 5.6J). The commonest system modification was subcutaneous coil (70 patients; Medtronic 6996SQ-58). Median follow-up was 1788 days. Kaplan-Meier survival curves of these two groups exhibited no significant difference in mortality between patients with and without system modification (Mantel-Cox Log-rank, p = 0.731).

Conclusions:
Patients with high DFT at ICD implant managed by system modification have mortality similar to patients without it. This questions the practice of system modification & calls for further analysis.
Abstract 19144: Fish Oil and Cyclooxygenase Inhibitors: a Novel Strategy to Manage Obesity-linked Dyslipidemia
Authors: Saraswathi Viswanathan , Perriotte-Olson Curtis , Heineman Robert D , Desouza Cyrus V
Published: July 2021

Introduction:
Dyslipidemia is a prevalent condition in obesity and type 2 diabetes. Although fish oil rich in omega-3 fatty acids (ω-3) is a widely used hypolipidemic agent, it is often required at high doses. At high doses, these fatty acids can induce oxidative stress or endothelial activation and therefore, strategies to improve their beneficial effects are needed. We previously reported that fish oil in combination with cyclooxygenase (COX) inhibitors exerts enhanced hypolipidemic and anti-inflammatory effects in low density lipoprotein receptor knock-out mice. Here, we sought to determine the effects of ω-3 fatty acids in combination with naproxen (NX), a COX inhibitor, on dyslipidemia and gene expression in subcutaneous adipose tissue (scAT) in humans.

Methods:
Obese dyslipidemic patients were randomly assigned to receive one of these interventions (n=8/group) for 12 wk: 1) Standard nutrition counseling (control), 2) ω-3 (2 g twice daily), 3) NX (220 mg twice daily), and 4) ω-3 (2 g twice daily) + NX (220 mg twice daily).

Results:
The body mass index, HOMA-IR, and plasma total, LDL, and HDL cholesterol levels were not altered significantly in any of the groups. The percent change in plasma

triglycerides (TG) from baseline was 75% (
P
<0.1) and 68% (
P
<0.05) in ω-3 and ω3 + NX-treated subjects, respectively. Notably, 25% of subjects who received ω-3s alone did not show a reduction in TG whereas all the patients that received ω-3 + NX showed a reduction in TG. Realtime PCR analysis of scAT showed that the expression of glucose transporter 4 (GLUT-4), a marker of glucose uptake and a key regulator of glucose homeostasis was significantly reduced in ω-3 compared to control group (
P
<0.01). However, combining NX with ω-3 abolished this effect. Moreover, the expression of MCP-1 and VCAM-1, markers of inflammatory response or endothelial activation, was significantly increased in ω-3 but not in ω-3 + NX group. The plasma levels of MCP-1 and E-selectin did not vary significantly in any of the groups.

Conclusions:
Our data reveal previously unrecognized effects of fish oil in scAT. Our data suggest that combining NX with ω-3 fatty acids will increase their effectiveness in reducing plasma TG and improve the benefits of ω-3 supplements by favorably altering gene expression in scAT.
Abstract 19263: Vasodilator Use and Wave Intensity Patterns in Hypertension
Authors: Chirinos Julio A , Zamani Payman , Rawath Deepa , Bhuva Rushik , Shiva kumar Prithvi , Peddireddy Shivapriya , Bhattacharya Priyanka , Ferrari Victor , Segers Patrick
Published: July 2021

Background:
Blood pressure is the result of interactions between the heart and the arteries. Although the effects of vasoactive blood pressure-lowering drugs on arteries has been widely investigated, their
in vivo
effects on ventricular-arterial interactions are not well understood.

Hypothesis:
We aimed to assess the relationship between antihypertensive drug use and ventricular arterial interactions assessed via wave intensity analysis (WIA), which quantifies the energy contained in waves generated by the heart and/or reflected from the periphery (figure).

Methods:
We studied 152 subjects with treated hypertension. We measured central pressure using carotid arterial tonometry. Ascending aortic flow was quantified with through-plane phase-contrast MRI. We performed WIA and assessed the relationship between specific classes of blood pressure lowering drug use and WIA patterns.

Results:
In models that adjusted for age, gender, body size, race, presence of diabetes and glomerular filtration rate, angiotensin receptor blocker (ARB) use was associated with a greater likelihood of a mid-systolic expansion (i.e., suction) wave (Hazard Ratio=31.1; P=0.005), whereas beta-blocker use was associated with a lower likelihood of such wave (HR=0.16; P=0.02). ARB use was also independently associated with a lower energy in the late systolic forward suction wave (Beta=-0.18; standardized beta=-0.24; P=0.007). This association persisted after adjustment for the forward compression wave (beta=-0.13; standardized beta=-0.16; P=0.008). No associations between WIA patterns and calcium channel blocker use, diuretic use, ACE inhibitor use or long-anting nitrate use were found.

Conclusions:
Wave intensity analysis is a useful tool to assess the effects of vasodilators on ventricular-arterial interactions. ARB use is selectively associated with systolic suction waves (from blood inertia), which may in turn unload the heart in mid and late systole.
Abstract 19277: Late Systolic Central Hypertension as a Predictor of Incident Heart Failure: the Multi-Ethnic Study of Atherosclerosis
Authors: Chirinos Julio A , Segers Patrick , Duprez Daniel A , Brumback Lyndia , Bluemke David , Kronmal Richard , Vaidya Dhananjay , Ouyang Pamela , Townsend Raymond , Jacobs David R
Published: July 2021

Background:
Experimental studies demonstrate that high aortic pressure in late systole relative to early systole, causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure.

Methods:
We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last 1/3 of systole) to early (first 2/3 of systole) pressure-time integrals (PTI) of the aortic pressure waveform, independently predicts incident heart failure (HF) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded non-invasively from 6,124 adults. The late/early systolic PTI ratio (L/ESPTI) was assessed as a predictor of incident heart failure (HF) during median 8.5 years of follow-up.

Results:
The L/ESPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95%CI=1.15-1.29; P<0.0001) even after adjustment for established risk factors for HF (HR=1.23; 95%CI=1.14-1.32: P<0.0001). In a multivariate model that included brachial systolic and diastolic blood pressure and other standard risk factors of HF, L/ESPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ESPTI was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF, the HR associated with hypertension was 1.39 (95%CI=0.86-2.23; P=0.18) whereas the HR associated with a high L/E was 2.31 (95%CI=1.52-3.49; P<0.0001). Cumulative hazard curves for HF among participants stratified according to the presence or absence of hypertension (prevalence=45%) or a high L/ESPTI (set empirically to an identical prevalence of 45% based on E/LSPTI) are shown in the figure.

Conclusions:
Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.
Abstract 19288: Pulmonary Hypertension and Sex Hormone Depletion Affect Lung and Right Ventricular Estrogen Receptor Expression
Authors: Frump Andrea , Fisher Amanda , Cucci Anthony , Albrecht Marjorie , Goss Kara , Tursunova Roziya , Whitson Jordan , Van Demark Mary , Presson Robert , Petrache Irina , Brown Mary Beth , Lahm Tim
Published: July 2021

Introduction:
Women with pulmonary arterial hypertension exhibit more preserved right ventricular (RV) function than men. The underlying mechanisms are unknown. We measured 17beta-estradiol (E2) levels and lung and RV expression of the two main estrogen receptors (ERalpha and -beta) in male and in intact or ovariectomized (OVX) female rats with Su5416/hypoxia (SuHx)-induced pulmonary hypertension (PH).

Hypothesis:
E2 is required for adaptation to increased RV afterload in females, and ER expression is inversely correlated with PH severity.

Methods:
Male and age-matched female Sprague-Dawley rats received Su5416 (20mg/kg), followed by 3 weeks of hypoxia (Patm=362 mmHg) and 4 weeks of room air. Selected females underwent OVX with or without concomitant E2 repletion (75 mcg/kg/d). RV hypertrophy (RV/[LV+S]), RV systolic pressure (RVSP), and PA muscularization were measured; complemented by echocardiographic assessment of RV function and measurement of exercise capacity (VO2max). In addition, we assessed RV pro-apoptotic signaling (bcl-2/bax; caspase-3 activity), serum E2 levels, and lung and RV ER expression by Western blot. N was 7-8/group. P<0.05 was considered significant.

Results:
While no sex differences were noted in RV/(LV+S), RVSP or PA remodeling, female SuHx rats exhibited more preserved cardiac indices (CI; p<0.05). OVX worsened SuHx-induced alterations in RV hypertrophy, RVSP and CI (p<0.05). In turn, E2 replacement in SuHx-OVX rats prevented SuHx-induced alterations in PH endpoints and RV function; this was accompanied by attenuated RV pro-apoptotic signaling. RV ERbeta decreased in OVX SuHx females, but was restored with E2 repletion (p<0.05). RV ERbeta correlated negatively with RVSP and RV/(LV+S), and positively with RV bcl-2/bax (p<0.05). Similarly, serum E2 levels correlated negatively with RVSP and RV/(LV+S) (p<0.05). While healthy females exhibited higher lung ERbeta than healthy males (p<0.05), no such differences were observed in SuHx-PH. Neither lung nor RV ERalpha was affected by PH or hormone depletion.

Conclusions:
E2 is required for female adaption to SuHx-PH, through a mechanism that may involve ERbeta-mediated RV cell viability signaling, thus allowing for better adaptation to increases in RV afterload.
Abstract 19292: The Efficacy of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Patients with Coronary Artery Disease and No Heart Failure in the Modern Statin Era: a Meta-Analysis of Randomized-Controlled Trials
Authors: Hoang Vu , Addison Daniel , Alam Mahboob , Virani Salim , Birnbaum Yochai
Published: July 2021

Background:
Data from randomized-controlled trials regarding the efficacy of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in patients with coronary artery disease (CAD) but no evidence of heart failure are inconclusive. Current ACC/AHA guidelines support their use in this population. The variation in efficacy of ACEi and ARBs in improving cardiovascular (CV) outcomes may be related to the rising use of statin therapy in the past two decades.

Methods:
We conducted literature review of randomized-controlled trials with ACEi or ARBs as the single intervention, focusing on studies involving patients with CAD including patients with left ventricular dysfunction but no clinical symptoms of heart failure. The MEDLINE database was searched for publications between 1/1/1980 and 12/31/2012 with searched terms including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, coronary artery disease, cardiovascular events, and myocardial infarction. Of the 1553 potentially relevant publications, 19 (14 ACEi and 5 ARB) met the inclusion criteria for a total of 99,631 randomized patients followed for a mean of 38 months. We evaluated the endpoints of CV mortality, all-cause mortality, non-fatal MI, and stroke. The relationship between endpoints across the 19 trials and the percentage of patients on statins in each trial (with available data) were evaluated using meta-regression analysis, expressed as highest standardized regression coefficient, Beta.

Results:
ACEi and ARB therapy across the 19 trials was associated with decreased CV mortality (OR 0.85; 95% CI 0.78-0.93) and all-cause mortality (OR 0.92; 95% CI 0.86-0.98). When adjusted for the percentage of statin, 46% of patients in the cohort, there was a significant linear decrease in the odds of CV mortality reduction with ACEi and ARB therapy (Beta = 0.01; p = 0.034).

Conclusion:
In patients with CAD and no evidence of heart failure, the additive benefits of ACEi and ARBs in decreasing CV mortality are blunted by statin therapy. The exact mechanism(s) for this result is unclear and further investigation is warranted. The modification of current ACC/AHA practice guidelines should be considered.