bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14231: Effectiveness and Safety of Statin Therapy in Children: A Multi-Center, Real-World Clinical Practice Experience
Authors: Kavey Rae Ellen W , Manlhiot Cedric , Collins Tanveer , Gidding Samuel S , Demczko Matthew , Clauss Sarah , Phillippi Ruth , Harahsheh Ashraf , Mietus-Snyder Michele , McCrindle Brian
Published: July 2021

Results of statin use in clinical practice in children are very limited, with effectiveness and safety data based on short-term clinical trials. To address this, we reviewed the results of all children with primary hypercholesterolemia treated with statins for more than 6 months from 4 Pediatric Lipid Clinics. Expert Panel guidelines recommend statin if LDL-cholesterol (LDL-C) exceeds 4.9 mmol/L (190 mg/dL), or 4.1 mmol/L (160 mg/dL) with additional risk factors, after 6 months of lifestyle modification, with hepatic enzyme monitoring plus clinical surveillance and CK measurement for myositis. Patients at all study sites were managed using these guidelines.

Results:
There were 246 pts (59% male) who had 1488 clinical assessments. Mean age at statin initiation was 12.5±0.5 yrs. Mean duration of therapy was 2.9 yrs (IQR: 1.9_4.7) with 48% more than 3 yrs. Initial statin prescribed varied over time but 61% of pts were started on atorvastatin and 70% remained on the first statin prescribed. Mean compliance was assessed at 92% and 234 pts (94%) remained on statin therapy at the end of the review. Baseline and follow-up lab values and anthropometry (mean
+
SD) appear below.

While 13 pts (5%) had transient AST or ALT > 3xULN, or CK >10xULN at some time during follow-up, no pt was diagnosed with myositis. In regression analysis adjusted for repeated measures over time, statin treatment was associated with significant reductions in total cholesterol, LDL-C and non-HDL-C with no change in HDL-C, TG, safety labs or anthropometry. Despite statin, 51% and 70% of pts had LDL-C levels above minimal (<3.35mmol/L; 130 mg/dL) and ideal (<2.85mmol/L; 110 mg/dL) targets at last follow-up.

Conclusions:
These findings in a large series of pts from real-world clinical practice show that statin therapy in children with primary hypercholesterolemia is safe and effectively lowers LDL-C on mid-term follow-up. Side effects are rare and discontinuation of treatment is uncommon.
Abstract 14244: Gender-Specific Association Between Serum Markers of Systemic Inflammation and Interstitial Cardiac Fibrosis: The Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Nauffal Victor , Ambale Venkatesh Bharath , Wu Colin , Bahrami Hossein , Tracy Russell , Cushman Mary , Bleumke David A , Lima Joao A
Published: July 2021

Introduction:
Inflammation contributes to pathogenic ventricular remodeling. Recently, T1 mapping has been used to non-invasively measure interstitial myocardial fibrosis. We examined the association between baseline markers of systemic inflammation and interstitial fibrosis measured using T1 mapping at 10 years follow-up in MESA.

Methods and Results:
1,156 participants underwent cardiac magnetic resonance imaging with T1 mapping. All analyses were stratified by gender. Three hierarchical multivariable linear regression models were constructed to assess the risk-adjusted association of baseline C-reactive protein (CRP), interleukin 6 (IL-6) and fibrinogen with 25 minutes post-contrast myocardial T1 time (T1Myo25). Shorter T1Myo25 reflect increasing levels of interstitial fibrosis. We found a non-linear relationship between IL-6 and T1Myo25 in males (Figure 1A). A significant negative association between T1Myo25 and increasing levels of IL-6 was found in males that reversed at IL-6 levels ≥2.7pg/ml. Moreover in males, increasing levels of fibrinogen were significantly negatively associated with T1Myo25, while a similar but non-significant trend was found for CRP (Figure 1B). In women, there was a similar inverse association between T1Myo25 and increasing levels of all three markers of systemic inflammation prior to adjusting for body mass index that became statistically non-significant following adjustment (Figure 1B). Similar associations with markers of inflammation were found using extracellular volume fraction and T1Myo12 as measures of interstitial fibrosis.

Conclusions:
Markers of systemic inflammation in males, particularly IL-6 and fibrinogen, are independently associated with increased interstitial fibrosis. In females, this association may be mediated by the obesity-induced inflammatory-state. These findings highlight the early role of inflammation in the pathogenesis of heart failure.
Abstract 14275: The Impact of Continuous and Interval Aerobic Exercise on Endothelium, Arterial Wall Properties and Inflammatory Status
Authors: Athanasiou Dimitrios , Siasos Gerasimos , Terzis Gerasimos , Stasinaki Aggeliki , Oikonomou Evangelos , Dimitropoulos Efstathios , Tsouroulas Stamatis , Gouliopoulos Nikolaos , Kokkou Eleni , Zisimos Konstantinos , Tourikis Panagiotis , Papageorgiou Nikolaos , Spengos Konstantinos , Tousoulis Dimitris
Published: July 2021

Introduction:
Chronic aerobic exercise training is associated with favorable long term cardiovascular effects.

Hypothesis:
We investigated the acute effects of continuous moderate-intensity aerobic exercise (CAE) and high intensity interval aerobic exercise (hIAE) on endothelial function, arterial stiffness and inflammatory status in healthy subjects.

Methods:
Twenty healthy men (mean aged 22.6±3.3yr) were recruited in this cross-over study. They participated in two exercise sessions: a) CAE: volume at 50% of maximum aerobic work on a cycle ergometer for 30 min and b) hIAE: interval maximum aerobic work on a cycle ergometer for 30 min. Endothelial function was evaluated by flow-mediated dilation (FMD) in the brachial artery. Carotid-femoral pulse wave velocity (cfPWV) and femoral-dorsalis pedis PWV (fdPWV) were measured as indices of central aortic and peripheral arterial stiffness. Intereleukin (IL)-17 levels were measured with ELISA. Measurements were carried out before and immediately after each exercise session.

Results:
There was no significant differences in baseline measurements before CAE and hIAE, regarding FMD, cfPWV and fdPWV and IL-17 levels (p=NS for all). Both CAE (8.57±2.55% vs. 6.37±1.48% p<0.001) and hIAE (8.48±2.60% vs. 5.95±1.78% p<0.001) significantly improved FMD, compared to baseline. The magnitude of FMD improvement was not different between CAE and hIAE (p=NS). Moreover, compared to baseline measurements, CAE (9.27±1.11m/sec vs. 8.17±1.48m/sec, p=0.003) and hIAE (9.14±1.07m/sec vs. 8.26±0.8m/sec, p<0.001) improved fdPWV. Though, CAE and hIAE had no impact in cfPWV, compared to baseline measurements (p=NS for both). Finally, there was no significant difference in IL-17 levels after CAE [11(9-17) pg/ml vs. 16(12-22)pg/ml, p=0.23] and hIAE [12(9-17)pg/ml vs. 14(9-15)pg/ml, p=0.61], compared to baseline measurements.

Conclusions:
Both CAE and hIAE can favorably affect to a similar extent endothelial function suggesting another cardioprotective effect of exercise on atherosclerosis progression. Though, these types of aerobic exercise have a different impact on central and peripheral arterial stiffness. Whether both types of exercise exert similar long-term effects merits further investigation.
Abstract 14299: The Prognostic Value of Insulin-like Growth Factor-Binding Protein 7 in Patients With Heart Failure and Preserved Ejection Fraction: Results From Irbesartan in Heart Failure and Preserved Ejection Fraction (I-PRESERVE) Trial
Authors: Gandhi Parul U , Chow Sheryl L , Rector Thomas S , Krum Henry , Gaggin Hanna K , McMurray John J , Zile Michael , Komajda Michel , McKelvie Robert S , Carson Peter E , Januzzi James L , Anand Inder S
Published: July 2021

Introduction:
Heart failure with preserved ejection fraction (HFpEF) is associated with considerable morbidity and mortality. Insulin-like growth factor-binding protein 7 (IGFBP7) is a cell cycle arrest biomarker associated with abnormal diastology and prognosis in HF with reduced EF (HFrEF). Its role in patients with HFpEF is unknown.

Hypothesis:
IGFBP7 will be associated with adverse outcomes in HFpEF.

Methods:
Baseline (BL) IGFBP7 (n=302; placebo=154, irbesartan=148) and 6 month change (Δ; n=293; placebo=147, irbesartan=146) were measured and correlated with clinical data, biomarkers, estimated glomerular filtration rate (eGFR), and the primary outcome of all-cause mortality (ACM) or cardiovascular hospitalization (CVH) in patients from the Irbesartan in HFpEF (I-PRESERVE) Trial; secondary outcomes included HF events.

Results:
Median BL IGFBP7 concentration was 218 ng/mL, higher than previously seen in patients with HFrEF. BL IGFBP7 was correlated with age (R
2
=0.13; P<0.0001) and other prognostic variables including amino-terminal pro-B-type natriuretic peptide (NT-proBNP; R
2
=0.22; P<0.0001) and eGFR (R
2
=0.14; P<0.0001). BL IGFBP7 was associated with the primary outcome (hazard ratio [HR]=1.06 per 10 ng/mL; P<0.001), ACM (HR=1.08 per 10 ng/mL; P<0.001), and HF events (HR=1.07 per 10 ng/mL; P<0.001;
Figure
) and remained significant for all outcomes after adjustment for NT-proBNP and eGFR. After 6 months, IGFBP7 did not change significantly in either treatment group. ΔIGFBP7 was not independently associated with outcomes but was associated with a decrease in eGFR in patients randomized to receive irbesartan (R
2
=0.09; P<0.002).

Conclusions:
IGFBP7 is associated with adverse outcomes in HFpEF. Further studies are needed to identify the mechanistic link between IGFBP7, renal function, and outcomes in patients with HFpEF.
Abstract 14317: Kvβ2 Mediates Cardiac Repolarization and Injury: Role of Pyridine Nucleotides
Authors: Chapalamadugu Kalyan C , Tur Jared , Cuevas Javier , Katnik Chris , Tipparaju Srinivas M
Published: July 2021

Background:
Voltage-gated potassium channel (Kv) β2 subunits (Kvβ2) belong to the aldoketo-reductase superfamily and associate with the Kv channel modulating its function. Also, Kvβ2 binds pyridine nucleotides (NAD[P]
+
/NAD[P]H) with high affinity altering Kv channel gating. However, the physiological relevance of Kvβ2 in cardiac health and disease is unknown.
Hypothesis:
We tested the hypothesis that Kvβ2 is essential to both basal and pyridine nucleotide mediated regulation of cardiac repolarization.
Methods and Results:
Kvβ2 knockout (KO) and wild type (Wt) mice were utilized for this study. ECG analysis showed prolonged QTc interval (74.7± 3.7 vs. 65.6 ± 3,
n=3
,
p<0.05
) in KO mice when compared to Wt. Monophasic action potential (MAP) data also showed prolonged duration (ms) at 50% repolarization level in KO mouse hearts vs. Wt (MAPD50; 13.2 ± 0.3 vs. 9.7 ± 0.6,
n=5-6
,
p<0.05
). To test the obligatory role of Kvβ2 in pyridine nucleotide modulation of cardiac repolarization, we exposed
ex vivo
perfused hearts or isolated cardiomyocytes to higher lactate levels. These data revealed that acute lactate exposure leads to significant but similar raise in NADH concentration [NADH]
i
in both KO and Wt heart tissue. However, marked repolarization deficits appeared only in Wt group when tested utilizing ex vivo perfused hearts (MAPD50 - Wt:11.5 ± 0.7
vs.
8.3 ± 0.5,
p<0.05
; KO:12.6 ± 0.7
vs.
12± 0.5,
p=0.5
, ms) or isolated myocytes (ΔAPD50 – Wt: 4.7±1.6 ms,
p<0.05
; KO:1.5 ± 0.7 ms,
p=0.1
). Perfusion with high pyruvate levels returned both [NADH]
i
and MAPD50 to basal levels in Wt mouse hearts. Similarly, we observed that a 14 day isoproterenol treatment also leads to significant increase in cardiac [NADH]
i
, but only the Wt mouse hearts showed significant repolarization deficits; ex-MAPD50 (5.5 ± 1.6,
p< 0.01
), when compared to no changes in KO (1.9 ± 0.9,
p< 0.1)
.
Conclusions:
Our results suggest that Kvβ2 regulates cardiac repolarization. Further, the differential repolarization changes despite similar increases in cardiac [NADH]
i
indicates an obligatory role of Kvβ2 in the pyridine nucleotide modulation of cardiac repolarization.
Abstract 14356: Blood Tests That Improve the Accuracy of a Brugada Syndrome Diagnosis
Authors: Zhou Anyu , Jinag Ning , Denegri Marco , Xie An , Shi Guangbin , Liu Hong , Liu Man , Ma Ruiyan , Jeong Euy-Myong , Napolitano Carlo , Priori Silvia , Dudley, Jr. Samuel C
Published: July 2021

Objectives:
To discover the role of altered gene expression regulation in Brugada Syndrome (BrS) and to find biomarkers for BrS diagnosis.

Methods:
Twenty-five control patients (Control), 25 BrS patients without SCN5A mutation (SCN5A(-)) and 20 BrS patients with SCN5A mutation (SCN5A(+)) were included in this study. Specified gene expression of white blood cells (WBC) were measured by RT-qPCR using TaqMan® Gene Expression assay.

Results:
MEF2C and MESP1 are the two major cardiac specific transcription factors expressed in WBC. The mRNA expression levels of SCN5A, MEF2C and HuR, one of mRNA stabilizers, were decreased in the SCN5A (+) group (P=0.047, 0.02, 0.000 vs. control group, respectively). The mRNA expression of MESP1 in WBCs was significantly lower in both SCN5A(-) (P=0.012 vs. control) and SCN5A(+) (P=0.000 vs. control) groups. There was no difference between the two BrS groups in MESP1 expression (P=0.215). The area under the Receiver Operating Characteristics (ROC) analysis curve for prediction of BrS using MESP1 levels was 0.775 (95% CI 0.668, 0.882, asymptotic Sig.=0.000). At the optimal cutoff, the corresponding maximum sensitivity and specificity were 0.62 (95% CI: 0.47, 0.76) and 0.88 (0.69, 0.97), respectively. The diagnostic odds ratio (DOR) of MESP1 for BrS diagnosis was 11.96 (95% CI: 5.79, 24.73). The assessment of the mRNA levels in blood SCN5A, MEF2C and HuR were useful for predicting BrS patients with an SCN5A mutation. The area under the ROC analysis curve for prediction of BrS with an SCN5A mutation using SCN5A, MEF2C and HuR mRNA levels in WBCs was 0.847 (95% CI 0.752, 0.942, asymptotic Sig.=0.000), 0.685 (95% CI 0.542, 0.828, asymptotic Sig.=0.016) and 0.777 (95% CI 0.652, 0.902, asymptotic Sig.=0.000), respectively. At the optimal cutoff, the DOR of SCN5A, MEF2C and HuR for SCN5A(+) BrS diagnosis was 17.5 (95% CI: 8.06, 37.86), 4.9 (95% CI: 2.61, 9.17) and 23.5 (95% CI: 9.39, 58.80), respectively.

Conclusions:
Our results suggest that assessment of circulating MESP1 may be used as a biomarker for BrS diagnosis while decreased SCN5A, MEF2C and HuR mRNA in WBCs is associated with BrS patients with an SCN5A mutation. Our results also suggest that decreased expression of SCN5A, MEF2C, MESP1, and HuR may be pathophysiologically related to BrS.
Abstract 14360: Gene Transfer of Sarco/Endoplasmic reticulum Ca2+-ATPase 2a Restores Pulmonary Artery Endothelial Catechol-O-Methyltransferase Activity to Decrease Norepinephrine Levels in Pulmonary Hypertension
Authors: Torquato Samantha , Aguero Jaume , Ishikawa Kiyotake , Hadri Lahouaria , Loscalzo Joseph , Maron Bradley A , Hajjar Roger J , Leopold Jane A
Published: July 2021

Elevated levels of norepinephrine (NE) may occur in pulmonary hypertension (PH), in part, when activity of catechol-
O
-methyltransferase (COMT) is decreased. COMT is expressed by pulmonary artery endothelial cells (PAEC), degrades NE, and is negatively regulated by aldosterone (ALDO) and cytosolic Ca
2+
. Expression of the cardiac isoform of the sarco/endoplasmic Ca
2+
-ATPase (SERCA2a) modulates ALDO and cytosolic Ca
2+
and is downregulated in pulmonary arteries in PH. We hypothesized that gene transfer of SERCA2a to pulmonary arteries would prevent the decrease in COMT activity and lower NE levels. Accordingly, human PAEC were infected with an adenovirus encoding SERCA2a to increase expression 4.2-fold (p<0.01) or control virus and exposed to ALDO (10
-7
mol/L), which decreases COMT activity by 59.2 ± 6.2% (p<0.01). Compared to controls, SERCA2a overexpression in PAEC had no effect on COMT mRNA or protein levels but increased COMT activity by 148.8 ± 14.5% (p<0.01) by decreasing cytosolic Ca
2+
levels by 38.2 ± 6.7% (p<0.05). This resulted in a decrease in NE levels in the medium (229.4 ± 20.6 vs. 139.9 ± 14.8 vs. pg/mg protein, p<0.01) and collagen I expression. To examine the in vivo relevance of SERCA2a gene transfer on COMT activity, the rat monocrotaline model of PH was treated with inhaled adeno-associated virus 1 carrying SERCA2a (AAV1.SERCA2a). There was no difference in COMT expression in AAVI.SERCA2a-treated or saline control PH-rats; however, lung COMT activity was increased 139.8 ± 8.2% (p<0.01) while lung levels of NE (366.7 ± 38.6 vs. 504 ± 30.2 pg/ml/mg, p<0.01), serum ALDO, and pulmonary artery collagen 1 were decreased by AAV1.SERCA2a. In the pig pulmonary vein banding model of PH, inhaled AAV1.SERCA2a gene therapy decreased mean pulmonary artery pressure (54 ± 20 vs. 29 ± 5 mmHg, p<0.03); increased COMT activity by 121.1 ± 6.2% (p<0.05); and decreased levels of ALDO by 43.3 ± 4.6% (p<0.03), NE by 43.3 ± 4.6% (p<0.03), and collagen I in remodeled vessels. Taken together, these data indicate that gene therapy with inhaled AAV1.SERCA2a increases COMT activity by decreasing intracellular Ca
2+
, thereby decreasing NE levels. This extends the actions of SERCA2a beyond pulmonary vascular remodeling in PH to modulating levels of circulating catecholamines.
Abstract 14445: Reduced Expression of Let-7f Leads to Impaired Ischemia-Induced Neovascularization Following Cigarette Smoke Exposure: Role of ALK5/SMAD2/PAI-1 Pathway
Authors: Dhahri Wahiba , Dussault Sylvie , Haddad Paola , Turgeon Julie , Tremblay Sophie , Desjarlais Michel , Mathieu Raphaël , Rivard Alain
Published: July 2021

Background:
Exposure to cigarette smoke is associated with impaired formation of new blood vessels (neovascularization) in response to ischemia. Here we investigated the potential role of miRs in that physiopathology.

Methods and Results:
Using Affimetrix GeneChip miRNA array analysis, we identified let-7f as a pro-angiogenic miR which expression is reduced following cigarette smoke exposure. qRT-PCR analyses confirmed that the expression of let-7f is significantly reduced in HUVECs treated with cigarette smoke extracts (CSE), and in the ischemic muscles of mice that are exposed to cigarette smoke (MES). In a mouse model of hindlimb ischemia, intramuscular injection of let-7f mimic restored ischemia-induced neovascularisation in MES. At day 21 after ischemia, Doppler flow ratios and capillary density in ischemic muscles were significantly improved in MES treated with let-7f mimic compared to those treated with a mimic control. Clinically, mice treated with let-7f mimic also exhibited reduced ambulatory impairment and hindlimb ischemic damages. Interestingly, we found that treatment with let-7f mimic can rescue endothelial progenitor cell (EPC) number and function (migration, integration into tubules) in MES. Let-7f has previously been shown to target ALK5 (TGF-βRI), an important modulator of angiogenesis. We found that ALK5 is significantly increased in HUVECs exposed to CSE and in the ischemic muscles of MES. This is associated with a downstream activation of anti-angiogenic factors such as SMAD2 and PAI-1. Importantly, treatment with let-7f mimic reduces the expression of ALK5, SMAD2 and PAI-1 both in vitro and in vivo. Moreover, let-7f mimic can also rescue angiogenesis in HUVECs exposed to CSE.

Conclusion:
Cigarette smoke exposure is associated with reduced expression of let-7f, which leads to impaired neovascularization following ischemia. Our results suggest that the mechanism involves increased activation of ALK5, together with a downstream stimulation of the anti-angiogenic SMAD2/PAI-1 pathway. Overexpression of let-7f using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in pathological conditions.
Abstract 14594: Gender Differences in Use of Anti-Coagulant For Atrial Fibrillation: A Report From the NCDR®
Authors: Thompson Lauren E , Maddox Thomas M , Bradley Steven M , Lei Lanyu , Grunwald Gary K , Peterson Pamela N , Masoudi Frederick A , Shimada Yuichi J , Turchin Alexander , Song Yang , Doros Gheorghe , Daugherty Stacie L
Published: July 2021

Background:
Women with atrial fibrillation (AF) have a higher risk of thromboembolism compared to men. In contemporary practice, whether rates of anticoagulation use according to thromboembolic risk vary by gender and if this relationship has changed over time with introduction of expanded treatment options (novel oral anticoagulants [NOACs]) are unknown.

Methods:
Using the outpatient National Cardiovascular Data Registry (NCDR) PINNACLE registry from 2010-2014, oral anticoagulation (OAC- warfarin or novel anticoagulant) use was compared in women and men with non-valvular AF and CHA2DS2-VASc scores ≥ 2. Patients with documented contraindications to anticoagulation were excluded. Multivariable logistic regression models assessed the association between gender and OAC use (at each CHA2DS2-VASc level) adjusted for demographic and clinical factors, and accounting for clustering by practice using generalized estimating equations. Temporal trends in OAC use were also compared.

Results:
Of the 658,341 patients with non-valvular AF and CHADS2VASc ≥2, 45.2% were women. The average CHADS2VASc score for women and men was similar (mean±SD, 3.4±1.16 vs 3.4 ±1.19, respectively, p = 0.245). At all thromboembolic risk levels women were less likely than men to have any anticoagulant prescribed (e.g. at CHA2DS2-VASc score = 4 53.4% of women vs. 56.1% of men received OAC), in adjusted analysis, RR 0.95, 95% CI 0.94-0.96, p <0.001(FIGURE). In temporal analysis, use of OAC increased over time in women and men (p < 0.001 for trend) with increased NOAC use in both genders (p <0.001 for trend).

Conclusions:
In this contemporary, ambulatory cohort of patients with non-valvular AF, women were slightly less likely to receive OAC across the spectrum of thromboembolic risk. Further studies are needed to understand the causes of these differences such as under-appreciation of gender as a risk factor or unequal treatment based on gender alone.
Abstract 14635: Exosomes Containing Archaeal DNA Are Increased in the Serum of Heart Failure Chagas’ Disease Patients
Authors: Higuchi Maria L , Kawakami Joyce T , Ikegami Renata N , Reis Marcia M , Ianni Barbara , Buck Paula , Mangini Sandrigo , Bocchi Edimar , Hajjar Ludhmila A
Published: July 2021

Introduction:
Exosome are microparticles smaller than 100nm, and have been described to prevent myocardial dysfunction. In accordance, we have found large amount of electron dense lipidic exosomes (EDexo) containing collagenase, in the serum of asymptomatic indeterminate form (IF) patients (pts) with Chagas’ disease (CD), in negative correlation with free collagenase. On the other hand, heart failure (HF) has been associated with increased levels of microparticles and we previously have detected pathogenic archaea in the myocardium of HFCD pts.

Hypothesis:
Demonstrate that exosomes present in the serum of HF CD pts are derived from archaea , being different from EDexo present in IF CD pts.

Methods:
Sera from 9 HF (07 males) and 13 from IF chagasic pts (04 males) were submitted to a gradient separation, with a mannitol/ sucrose rich solution. After centrifugation, the supernatant samples were rich in ED exosomes, which were studied by in situ hibridization at electron microscopy, using archaea DNA probe ARCH915. The numbers of EDexo and archaea DNA dots were counted in 4 photos representing the richest places of each case in x50K magnification. Comparison between HF and IF was performed by T test or Mann Whitney and correlation by Spearman test. A difference P<0.05 was considered significant.Results: HF group presented lower numbers of ED exo than IF (5.6 ± 8.3 vs 42.5 ± 56.6),
P
<0.001, however their EDexo contained higher amount of archaeal DNA dots (1.5 ± 3.0 vs 0.2 ± 0.5,
P
=0.02). A higher amount of extracellular archaeal DNA in HF than IF (63.0 ± 150 vs 11.1 ± 13.1,
P
<0.001) had positive correlation with numbers of EDexo (r=0.66,
P
=0.01), but not in IF(r=0.29,
P
=0.10).

Conclusions:
EDexo present in the serum of HF CD pts are carrying and seem to release archaeal DNA, differently from those present in asymptomatic IF CD pts, which do not contain archaeal DNA and could have a protective role removing abnormal proteins linked to development of HF.
Abstract 14645: Three Dimensional Ejection Fraction is More Strongly Determined by Strain Than by Torsion in a Cohort of Breast Cancer Patients Undergoing Anthracycline-Based Chemotherapy
Authors: Gulati Gaurav , French Benjamin , Zhang Kathleen W , Narayan Hari K , Bajulaiye Akinyemi , Zhang Carina , Hyman David , Ky Bonnie
Published: July 2021

Introduction:
Anthracycline cardiotoxicity affects approximately 10-20% of treated individuals, representing a significant health burden. Three dimensional (3D) echocardiographic measures of myocardial mechanics have the potential to improve our understanding of the functional changes that occur with anthracyclines, and may play an important role in cardiotoxicity risk prediction. Our objective was to define the relationships between 3D myocardial deformation parameters and left ventricular ejection fraction (LVEF) in a longitudinal, prospective cohort of patients with breast cancer.

Methods:
We performed 3D echocardiograms at standardized intervals in a longitudinal cohort of women with breast cancer undergoing doxorubicin therapy with or without trastuzumab. We acquired all 3D images at a minimum of 22 frames per second and excluded from analysis all images that had poor tracking of greater than 3 myocardial segments, dropout of the apex, or stitch artifact. Two readers used a vendor-independent analysis platform (TomTec Cardiac Performance Analyses, Unterschleissheim, Germany) to measure 3D LVEF and the following 3D deformation parameters: principal strain, global longitudinal strain (GLS), global circumferential strain (GCS), and left ventricular torsion. Spearman correlation analyses were performed to understand the relationships amongst these parameters.

Results:
We analyzed 270 total echocardiograms from 87 women (mean age 49). Conventional 3D strain parameters were highly correlated with 3D LVEF (principal strain, r=-0.95, p<0.001; GLS, r=-0.85, p<0.001; GCS r=-0.97, p<0.001). In contrast, left ventricular torsion was only modestly correlated with 3D LVEF (r=0.51, p<0.001).

Conclusions:
Three dimensional principal strain, GLS, and GCS were all strongly correlated with 3D LVEF. However, left ventricular torsion was only weakly correlated to LVEF, suggesting that LVEF is determined less by torsion than by 3D strain. With further study, 3D strain may play an important role in chemotherapy cardiotoxicity risk prediction.
Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure
Authors: Morine Kevin , Paruchuri Vikram , Qiao Xiaoying , Mackey Emily , Aronovitz Mark , Alcaide Pilar , Blanton Robert , Karas Richard , Kapur Navin K
Published: July 2021

Introduction:
Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure.

Methods and Results:
ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC.

Conclusions:
Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.
Abstract 14669: Prevalence of Elevated Lp(a) Levels in 629,858 Subjects From a Referral Laboratory Population in the United States
Authors: White Justin , Varvel Steve , Tsimikas Sotirios
Published: July 2021

Background:
Elevated Lp(a) is now accepted as a causal, independent risk factor for cardiovascular disease. Data suggest that ~20% of subjects living in the Copenhagen area have elevated Lp(a) levels (>50 mg/dL. Lp(a) <50 mg/dL has been recommended as a desirable level, but similar large datasets in varied populations have not been available from other countries.

Methods:
We analyzed fasting Lp(a) in 629,858 subjects from the large referral dataset from Health Diagnostic Laboratory measured in years 2010 to 2014 to assess prevalence of elevated Lp(a). Lp(a) mass levels were measured by immunoturbidometric assay and expressed as mg/dL.

Results:
Median age of the subjects was 56, and 53.7% were female. Lp(a) levels were skewed rightward (Figure). The mean±SD levels were 31±38 mg/dL and median (IQR) levels were 15 (7-43) mg/dL, with range 0-571 mg/dL. Females had higher median (IQR) Lp(a) levels than males [16 (8-47) vs. 13 (6-38), p<0.0001]. Lp(a) percentile levels at 75%, 80%, 90%, 95% and 99% were >43 mg/dL, >55 mg/dL, >85 mg/dL, >109 mg/dL, and >169 mg/dL, respectively. Lp(a) levels >30 mg/dL and >50 mg/dL were present in 31.8% and 21.8% of subjects, respectively

Conclusion:
This is the largest database to assess the distribution of Lp(a). Lp(a) levels >30 and >50 mg/dL were common, constituting 31.8% and 21.8% of this referral laboratory population, and are consistent with the Copenhagen data. These data will help to define new global guidelines and therapeutic targets for new Lp(a) lowering therapies, such as antisense oligonucleotides directed to apo(a).
Abstract 14677: Oxidative Damage in Failed Clinical Bioprosthetic Heart Valve Explants
Authors: Lee Suengwon , Ferrari Giovanni , Levy Robert J
Published: July 2021

Introduction:
Bioprosthetic heart valves (BHVs), fabricated from glutaraldehyde-fixed bovine pericardium or porcine aortic valves, have been widely used in valve replacement surgery. However, BHVs fail over time due to structural degeneration. Despite frequent observations of calcification-associated BHV failure, more than 25% of BHV structural failures occur without calcification. Previously, we reported that oxidative stress may have a pivotal role in noncalcific BHV failure. Moreover, oxidation-induced formation of dityrosine (DT) crosslinks via hydroxyl- and tyrosyl-radical mediated pathways was only detected in clinical BHV explants. Yet the mechanism of DT formation and its role in structural degeneration of clinical BHV is incompletely understood.

Hypothesis:
Oxidative damage to BHV is due to a specific spatial localization of DT crosslink formation mediated by myeloperoxidase (MPO) and/or iron (Fe) deposition in clinical BHV explants

Method & Results:
BHVs from 7 human subjects were collected and subjected to mass spectrometry to measure DT in paraffin sections of BHV. 4 different regions of each BHV leaflet (free edge, sewing cushion, commissure, and middle region) were sampled as well as entire cross-sections of each cusp. DT was only detected in the mid–cusp (137.37±49.96 μmol/mol) and was not significantly different from DT quantitated in the cross-sections (191.29±65.98 μmol/mol). DT was not detected in other regions, implying a specific spatial localization of oxidative stress in BHV. MPO, a neutrophil derived enzyme, is responsible for reactive oxygen species (ROS) generation. Immunofluoresence microscopy demonstrated significant presence of MPO in the BHV, implying that MPO may be responsible for the DT formation in BHV. Fe deposition due to intracuspal hematomas and/or Fe-association with calcific deposits can also be responsible for ROS and DT formation. Fe was shown to be present in histology sections in failed BHV by Prussian Blue staining, indicating that Fe deposits may also in part be responsible for the observed DT formation.

Conclusion:
These results demonstrated a mid-leaflet localization of DT formation in clinically failed BHV explants. This may in part be mediated by MPO and/or Fe-deposits in clinical BHV.
Abstract 14733: Influence of High Risk Adrenergic Receptor Genotypes on Outcome in Infants With Single Ventricle
Authors: Ramroop Ronand , Manase Dorin , Manase George , Simmons Cory , Newburger Jane W , Gaynor J William , Russell Mark W , Mital Seema
Published: July 2021

Introduction:
Variants in adrenergic receptor (ADR) genes are associated with adverse clinical outcomes in patients with heart failure. We evaluated the association of variants in ADR receptor genes with outcomes in infants with single ventricle lesions.

Methods:
Infants with single ventricle lesions participating in the Pediatric Heart Network Single Ventricle Reconstruction Trial (randomized to Norwood with modified Blalock-Taussig shunt versus right ventricle-pulmonary artery shunt) underwent genotyping for 4 single nucleotide polymorphisms (SNPs) in 3 ADR genes: ADRB1-A/G (rs1801252), ADRB1-C/G (rs1801253), ADRB2-C/G (rs1042714) and ADRA2A-C/T (rs553668). Linear and logistic regression, deviance tests, t-tests and F-tests were used to analyze association of genotype with clinical outcomes including hospital length of stay (LOS) at Norwood, occurrence of serious adverse events (SAE), and transplant-free survival during 14 months follow-up using a dominant model.

Results:
The study included 347 eligible patients (62% male; 83% white). The mean age at Norwood procedure was 6±3.6 days and median Norwood LOS was 8 days. During 14 months follow-up, 147 patients had SAEs, 94 patients died and 14 were transplanted. ADRB1 AA (rs1801252) genotype was associated with longer Norwood LOS. The difference in LOS between AA vs AG/GG was 7.99 days (confidence intervals, 0.27, 15.71; p=0.043). ADRA2A CC (rs553668) genotype was associated with higher odds of SAEs i.e. 103/216 (47.6%) in CC compared to 36/106 (34%) in CT/TT [Odds ratio 1.77 (confidence intervals, 1.09, 2.87), p=0.018]. Transplant-free survival was not different between genotype groups. Combined analysis of risk genotypes did not confer an additive risk of adverse outcomes.

Conclusions:
ADR genotypes known to cause adrenergic upregulation were associated with prolonged Norwood hospitalization and/or serious adverse events in infant single ventricles. This may be secondary to adverse effects of adrenergic overexpression on cardiac function and systemic hemodynamics. Analysis is ongoing to replicate these findings for utility as predictive markers for outcomes in infant single ventricles.
Abstract 14766: Pulmonary Vein Isolation Alone is Not Superior to Amiodarone for the Treatment of Persistent Atrial Fibrillation in Patients With Congestive Heart Failure and an Implanted Device: Results From the AATAC Randomized Trial
Authors: Di Biase Luigi , Mohanty Prasant , Mohanty Sanghamitra , Santangeli Pasquale , Trivedi Chintan , Lakkireddy Dhanujaya , Reddy Madhu , Jais Pierre , Themistoclakis Sakis , Dello Russo Antonio , Casella Michela , Pelargonio Gemma , Narducci Maria Lucia , Schweikert Robert , Neuzil Petr , Sanchez Javierr , Horton Rodney , Beheiry Salwa , Hongo Richard , Hao Steven , Rossillo Antonio , Forleo Giovanni , Tondo Claudio , Burkhardt J. David , Haïssaguerre Michelle , Natale Andrea
Published: July 2021

Introduction:
The best treatment option for the management of patients (pts) with heart failure (HF) and persistent AF is unknown. The AATAC trial showed that catheter ablation (CA) is superior to Amiodarone in achieving freedom from AF at follow up. In this analysis we present the outcome sorted by type of AF procedure.

Methods:
AATAC was a randomized multicenter study. Pts with persistent AF, dual chamber ICD or CRTD, NYHA II-III and LV EF <40% within the last 6 months were randomly assigned (1:1 ratio) to undergo CA for AF (group 1=102 pts) or receive AMIO, (group 2=101 pts). Recurrence of AF was the primary end point. Based on operator’s choice patients could undergo pulmonary vein isolation alone (PVI) or PVI plus posterior wall plus non PV trigger ablation (PVI+PW+NPV) as detected by high dosage of isoproterenol.

Results:
PVI was performed in 22 patients undergoing ablation, while PVI+PW+NPV ablation was performed in 80 patients. Baseline characteristics were not different between the groups. At 26±8 months follow-up, the success rates in PVI, PVI+PW+NPV, and AMIO groups were 8 [36.4%] and 63 [78.8%] and 34 (34.0%) respectively, p<0.001 (figure). Patients receiving PVI+PW+NPV ablation, showed significantly higher success than those with PVI alone or amiodarone (p <0.001). The outcome in the PVI alone group was not different from AMIO group (p= 0.67). No patient was lost to follow-up during the study period. At the time of analysis, all recurrence-free patients had completed ≥6 month follow-up.

Conclusion:
This randomized study shows that PVI alone has a low success rate similar to Amiodarone when compared to PVI plus posterior wall plus non pv trigger in patients with heart failure and persistent AF.
Abstract 14780: The First Hundred Days: Gender Differences in Psychosocial Distress After Heart Transplant
Authors: Doering Lynn , Chen Belinda , Hickey Kathleen , Carter Erik , Castillo Carmen , Pickham David , Mancini Donna , Deng Mario , Kobashigawa Jon , Drew Barbara
Published: July 2021

Early psychological distress after heart transplant (HTx) is associated with adverse outcomes (e.g. poorer medical compliance, higher risk of infection). In the HTx population, gender effects of depression and anxiety symptoms are controversial. Our objective was to examine gender differences in psychosocial measures early after HTx.

Methods:
We enrolled 91 adult HTx patients (29% female, mean age=51 ± 14 years) who completed measures of depression (Patient Health Questionnaire [PHQ]-9), anxiety (Brief Symptom Inventory [BSI]), perceived control (Control Attitudes Scale-Revised) and quality of life (QOL) (RAND-36 Health Survey) in the first 100 days after HTx (mean time from HTx = 50 ± 24 days). Hierarchical multiple linear regression models were used to examine gender influences on depression, anxiety, control, and QOL.

Results:
Compared to men, women are more likely to experience high depressive symptoms (15% vs. 39%, p=0.02), high levels of anxiety (46% vs.77%, p=0.008), and low perceived control (average score 33 vs. 29, p=0.007). For both men and women, anxiety is more prevalent than depressive symptoms (Figure). Compared to men, women had lower QOL due to pain (p=0.045) and limitations from emotional problems (p=0.02). In linear regression analyses, the effect of gender remained significant on depression (p=0.003), anxiety (p=0.03), and perceived control (p=0.02), but not QOL, after controlling for demographics (age, marital status, race, time between HTx and questionnaire completion, and Charlson Comorbidity Index).

Conclusion:
In the first 100 days after HTx, women experience more depressive and anxiety symptoms and less control over their heart health than men. Clinicians should monitor these symptoms early after HTx, especially in women. Development of gender-specific interventions aimed at a smooth post-HTx transition are warranted. Future research is needed to evaluate the relationship of anxiety and depressive symptoms before and after HTx.
Abstract 14808: Bleed Outcomes Following Coronary Artery Stent: Risk Associated With Combined Antithrombotic Therapy Common in Atrial Fibrillation: Insights From Medicare Claims Data
Authors: Dadekian Gregory A , Smith Jeremy , Kaplan Aaron V , Morden Nancy E
Published: July 2021

Background:
Platelet inhibitor (PI) use following coronary artery stent confers bleed risks, especially for atrial fibrillation (AF) patients on oral anticoagulants (OAC), a subgroup often excluded from randomized stent trials. We studied a national sample of elderly stent recipients to quantify bleed risks associated with combined OAC and PI, pharmacotherapy common in AF.

Methods:
Using a 40% Medicare random sample denominator file and associated inpatient, outpatient (2003-2012) and prescription (2006-2012) claims, we studied patients age 65 and older receiving a coronary artery stent. We measured OAC and/or prescription PI use after stent placement. Cox regression models estimated risk of bleed events adjusting for individual characteristics, morbidities, and time-varying medication use.

Results
Overall, 165,718 patients in our sample received a stent, 2006-2012; 20.4% had AF; mean age was 73.8 (SD 6.3). In the first month post-stent, among AF patients, 40.7% received OAC, 85.6% prescription PI, 35.9% both; among non-AF patients corresponding use was 3.5%, 90.3% and 3.1% respectively. At 13 months post stent, 61.0% of AF patients and 71.1% of non-AF patients continued using prescription PIs while 15.5% and 1.7% respectively remained on both PI and OAC therapy. Compared to those taking only prescription PIs, the risk of bleeding associated with warfarin plus PI was 2.05 (95% CI: 1.97 - 2.13); the risk associated with novel OACs (dabigatran or rivaroxaban) plus PIs was 2.60 (95% CI: 2.26 - 2.99).

Conclusions:
In a national, older population combined OAC and PI use following stent is common in AF patients and associated with bleeding risk. These findings should inform stent selection and antithrombotic strategies. The association between novel OACs and bleeding was unexpected and warrants further exploration as these products gain use.
Abstract 14827: Nitric Oxide During Cardiopulmonary Bypass Improves Clinical Outcome: A Blinded, Randomized Controlled Trial
Authors: James Christopher S , Horton Stephen , Brizard Christian , Molesworth Charlotte , Millar Johnny , Butt Warwick
Published: July 2021

Background:
Children requiring cardiac surgery with cardiopulmonary bypass (CPB) frequently develop Low Cardiac Output Syndrome (LCOS), particularly when very young, A pilot study of 16 children by Checchia et al. (2013) showed that the delivery of nitric oxide (NO) to the CPB circuit shortened duration of mechanical ventilation and ICU stay. We hypothesized that administering NO to oxygenator gas flow during CPB would decrease the incidence of LCOS and effect subsequent clinical outcomes.

Methods:
We conducted a prospective, blinded, randomized controlled trial in children with congenital heart disease having surgery with CPB. Randomization was stratified by age and ‘blocked’ at six in each group. Children received oxygen alone or 20 ppm gaseous NO and oxygen to the CPB gas administration line. Only the study perfusionist was aware of the allocation and all equipment and devices were otherwise identical in each group; in particular the cardiac surgeon and anesthetist remained blinded to patient allocation.

Results:
198 children were enrolled following written consent. There were no differences in patient characteristics, diagnoses or surgeries between groups. 101 children received NO and had a significant reduction in LCOS (14% vs 31%, p=0.004), use of ECMO (1% vs 8%, p=0.014) and a non-significant reduction in ICU length of stay (48hrs vs 72hrs, p=0.111), compared to the 97 children who did not receive NO. The reduction in LCOS was most pronounced in children less than 6 weeks of age (20% vs 52%, p=0.012) and in those aged 6 weeks to 2 years (6% vs 24%, p=0.026), who also had significantly reduced ICU length of stay (43hrs vs 84hrs, p=0.031). LCOS occurred equally between groups in children greater than 2 years of age (17% vs 21%, p=0.678). There was no difference in the amount of post-operative bleeding in any age group. Children greater than 2 years of age who received NO required fewer blood transfusions (8.3% vs 24.1%, p=0.096).

Conclusions:
Delivery of NO to the CPB circuit for children undergoing cardiac surgery significantly reduces the incidence of LCOS, use of ECMO and ICU length of stay by varying degrees, according to age group.
Abstract 14888: Lipid Changes 8 Years Post Gastric Bypass in Adolescents With Severe Obesity
Authors: Shah Amy S , Jenkins Todd , Urbina Elaine M , Kirk Shelley , Siegel Robert , Inge Thomas
Published: July 2021

Introduction:
Severe obesity in adolescents is increasing and few effective treatments exist. Weight loss surgery is one option, but the extent to which surgery influences cardiovascular risk factors such as lipids in youth is not clear. We studied the impact of weight loss surgery in adolescents with severe obesity on lipid parameters in the Follow-up of Adolescent Bariatric Surgery-5+ (FABS-5+) study >5 years postoperatively.

Hypothesis:
We predicted weight loss surgery would be associated with a greater improvement in lipids compared to no surgery.

Methods:
Adolescents and young adults who either underwent laparoscopic Roux-en Y gastric bypass (RYGB; “Surgical”) or who were seeking weight loss treatment (“Non-Surgical”) in 2001-2007 were recruited for the FABS-5+ follow-up study between 2011-2013. Baseline (pre-treatment) BMI and fasting lipids and TG/HDL-C ratio (representing small dense LDL particles) were abstracted from charts. Follow-up data were obtained at a research visit. Changes in BMI and lipids were evaluated using paired t-tests and Wilcoxon signed rank tests.

Results:
At baseline, surgical participants (n=58; 80% of all RYGB cases performed in 2001-2007) were a mean±SD age of 17±2 years and 25±2 at follow-up. 86% were Caucasian and 64% were female. After RYGB, BMI was 29% lower than baseline (p<0.01). All lipids (except total cholesterol) significantly improved with the largest changes in HDL-C and TG/HDL-C ratio. In the non-surgical comparison group (n=30) from baseline to follow up (ages 15±2 and 22±2 years, respectively), BMI increased by 8% but lipid parameters were similar (Table).

Conclusions:
This is the longest term and most complete follow-up of youth following RYGB. Weight loss was durably maintained and significant improvements in lipid profile were observed. Whether these lipid improvements translate into reductions in atherosclerosis and cardiovascular events overtime remains to be determined.