bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 16017: Mid-term Outcomes in Persistent and Long-standing Persistent Atrial Fibrillation Patients Undergoing Rotor Ablation
Authors: Gianni Carola , Metz Tamara , Di Biase Luigi , Mohanty Sanghamitra , Trivedi Chintan , Gökoglan Yalçin , Günes Mahmut F , Bai Rong , Al-Ahmad Amin , Burkhardt J D , Gallinghouse Joseph G , Horton Rodney , Hranitzky Patrick M , Sanchez Javier E , Tomassoni Gery , Halbfaβ Philipp , Müller Patrick , Schade Anja , Deneke Thomas , Natale Andrea 
Published: July 2021

Introduction:
Focal impulse and rotor modulation (FIRM)-guided ablation targets localized sources that are thought to sustain AF. We sought to evaluate if acute success of FIRM-guided ablation in patients with non-paroxysmal AF influenced the mid-term ablation outcomes.

Methods:
This was a multicenter prospective observational study of persistent and LSP AF patients undergoing FIRM ablation in 3 centers. Patients with at least 2 months follow-up were included in the analysis.

FIRM was performed alone or in addition to conventional ablation and rotors were ablated as confirmed by their absence during remapping. Acute success was defined as AF termination, organization or slowing 10%. Mid-term success was defined as freedom from AT/AF off antiarrhythmic drugs (AADs) and after a single procedure during the initial follow-up (excluding the 2-month blanking period).

Results:
A total of 43 patients were enrolled (mean age 62 ± 10; 91% persistent, 9% LSP). Rotors-only ablation was performed in 65% of patients, and in addition to conventional ablation in the remaining 35%. Overall, acute success was achieved in 33% of patients.

During a mean follow-up of 5.5 ± 2.4 months, 35% of patients were free of AT/AF off AADs after a single procedure. When comparing patients who underwent rotors-only ablation with those who received additional conventional ablation, mid-term success rates were respectively 25% vs. 53% (P = NS).
There was no statistical difference in SR maintenance between patients with and without acute success during FIRM ablation (29% vs. 38%, P = NS).

Conclusion:
FIRM-guided ablation in persistent and LSP AF was not effective in obtaining AF slowing/organization/termination during the procedure and in preventing mid-term AT/AF recurrences. Acute success did not impact the mid-term success rate.
Abstract 16761: Long Non-coding RNA Meg3 Controls Endothelial Cell Function: Implications for Endothelial Aging and Senescence
(Best of Basic Science Abstract)
Authors: Boon Reinier , Hofmann Patrick , Michalik Katharina , Knau Andrea , Ponomareva Yuliya , Zeiher Andreas , Uchida Shizuka , Dimmeler Stefanie 
Published: July 2021

The majority of transcribed RNA does not encode proteins, but may function as regulatory RNA. Long non-coding RNAs (lncRNAs) have been described to play an important role in many biological processes, including epigenetic regulation of gene expression.
To determine the expression and functional role of lncRNAs in endothelial cells, we performed RNA deep sequencing of human umbilical venous endothelial cells (ECs). Among the highest expressed lncRNAs, we identified Meg3 (35.3±0.6 RPKM), which was increased in replicative senescent HUVECs in vitro (passage 16/17 vs 2/3, 2.9±0.99-fold). Interestingly, Meg3 is induced in the intima of aged mice and correlates with age in human hearts (p=0.016). In HUVECs, Meg3 localizes to the nucleus and is also induced by hypoxia (4.08±0.78-fold, p<0.05). Silencing of Meg3 using LNA-GapmeRs induced angiogenic sprouting and proliferation of endothelial cells in vitro (1.4±0.14-fold, P<0.05) and repressed SA-β-galactosidase activity. Conversely, lentiviral overexpression of Meg3 inhibited sprouting angiogenesis and cell cycle progression, although splicing isoforms of Meg3 show differential effects.
Mechanistically, RNA immunoprecipitation showed that Meg3 associates specifically to H3K27me3, a silencing chromatin mark, and interacts with EZH2, a histone methyl transferase. Silencing of Meg3 in HUVECs represses, and overexpression of Meg3 induces, global gene expression, as measured by exon array analysis. As Meg3 was described to recruit Jarid2 to chromatin, we determined whether Meg3 requires Jarid2. The Meg3 loss-of-function induced repression of proliferation was normalized after silencing Jarid2, indicating that Meg3 effects are at least partly Jarid2-dependent. Finally, silencing of Meg3 in aged mice in vivo using gapmeRs in combination with hind limb ischemia significantly repressed Meg3 levels in the hindlimb and induced recovery of perfusion compared to control mice. Capillary and arteriole density was also markedly induced after silencing Meg3.
These results demonstrate that silencing Meg3 may be a potential strategy to reduce endothelial senescence or increase regenerative angiogenesis.
Abstract 17070: Efficacy and Safety of Alirocumab: Pooled Analyses of 1048 Individuals With Diabetes Mellitus From Five Placebo-controlled Phase 3 Studies of at Least 52 Weeks Duration
Authors: Ginsberg Henry N , Farnier Michel , Robinson Jennifer G , Cannon Christopher P , Sattar Naveed , Baccara-Dinet Marie T , Lorenzato Christelle , Bujas-Bobanovic Maja , Louie Michael J , Colhoun Helen M 
Published: July 2021

Background:
Individuals with diabetes (DM) are at high risk for CVD and may not achieve adequate control of LDL-C levels with current lipid-lowering therapies.

Aim:
To assess alirocumab (ALI) efficacy and safety in individuals with and without baseline DM.

Methods:
Five placebo (PBO)-controlled Phase 3 studies of 52-78 weeks were analyzed, comprising 1048 individuals with DM at study entry and 2444 with no DM (safety population). All individuals had hypercholesterolemia, and were on maximally tolerated background statin therapy. Efficacy data were pooled by initial ALI dose; 3 studies (n=1043, ITT analysis) used PBO or ALI 75 mg every 2 weeks (Q2W), increasing to 150 mg Q2W at W12 if LDL-C at W8 ≥ 70 mg/dL; 2 studies (n=2416, ITT analysis) initiated treatment with PBO or ALI 150 mg Q2W. All doses were 1 mL SC injection. Safety data were pooled for all 5 studies. Efficacy data are reported to W24, safety for ≥52 weeks.

Results:
Individuals with DM had lower mean baseline LDL-C levels. At W12, ALI 75 mg Q2W significantly reduced LDL-C levels from baseline vs PBO with treatment effect consistent regardless of DM status (Table). A higher proportion of participants with no DM received a dose increase at W12, leading to a greater magnitude of reduction at W24 in that group.

For those initiating at ALI 150 mg Q2W, LDL-C reductions of 58.3% (DM) and 62.3% (no DM) vs PBO were achieved at W24 (Table).
Improvements were seen in other parameters, including TGs, HDL-C, and Lp(a), largely irrespective of baseline DM status.
Adverse event (AE) rates were generally comparable in both groups. AEs occurring in ≥5% of individuals in all subgroups were nasopharyngitis and URI. Injection site reactions (ISRs) were less frequent in those with DM: ALI 3.6% and PBO 2.8%, vs no DM: ALI 8.4% and PBO 6.1%.

Conclusions:
ALI demonstrated robust LDL-C reductions in individuals with and without DM. Safety observations were generally similar regardless of DM status, although those with DM reported fewer ISRs than those without.
Abstract 17135: Distribution of Anti-oxidative Activity During Remodeling of High Density Lipoprotein: Studies With CSL112
Authors: Cukier Alexandre M , Diditchenko Svetlana A , Navdaev Alexei V , Spycher Martin O , Chapman M J , Wright Samuel D , Kontush Anatol 
Published: July 2021

We have previously shown that reconstituted HDL has the ability to inactivate phospholipid hydroperoxides (PLOOH) in oxidized LDL by virtue of redox-active Met residues present in apolipoprotein A-I (apoA-I), with the level of activity being proportional to the amount of apoA-I protein added. CSL112 is human apoA-I, reconstituted with phosphatidylcholine to form HDL particles suitable for infusion. Infusing CSL112 into human subjects or adding it to human plasma ex vivo, causes remodeling of endogenous HDL. Similar remodeling occurs upon incubation of CSL112 with purified HDL3 and results in accumulation of three HDL species: enlarged HDL (HDL2), a smaller, dense species (HDL3c-like), and lipid-poor apoA-I (pre-β1 HDL). Here we examine the distribution of anti-oxidant activity upon remodeling of native plasma HDL induced by CSL112.
We incubated CSL112 with human plasma HDL3, isolated the three populations of remodeled HDL particles by density gradient ultracentrifugation and compared (on a total protein basis) their ability to inactivate PLOOH derived from oxidized LDL as well as their apoA-I content of unoxidized and oxidized Met residues.
Both parent CSL112 and HDL3 displayed anti-oxidative activity, inactivating 22±4 and 47±9% of PLOOH, respectively (n=4). Upon remodeling, this activity was mainly found in enlarged HDL2 and smaller HDL3c-like species (PLOOH inactivation, 46±3 and 47±9%, respectively) and was low (23±17%) in lipid-poor apoA-I. In parallel, apoA-I Met residues were oxidized in HDL; oxidation was several fold lower in the lipid-poor apoA-I (12±3%) compared to larger species (62±1% and 69±2% in HDL2 and HDL3c-like particles), consistent with a limited accessibility of apoA-I Met to PLOOH molecules in the lipid-poor particles.
These studies further confirm the unequal distribution of HDL function among HDL subclasses and emphasize the important role of HDL remodeling in the production and maintenance of HDL functionality. The antioxidant properties of CSL112 add to its potential as a promising therapy for reducing the high risk of early recurrent atherothrombotic events following acute MI (AMI). A Phase IIb trial (AEGIS-I; NCT02108262) of CSL112 in AMI patients is ongoing.
Abstract 17462: Relevance of Regulatory T Cells to Gender Dimorphism in Pulmonary Hypertension
Authors: Tamosiuniene Rasa , Nguyen Linh , Luria Ayala , Sante Joshua , Saito Toshie , Rabinovitch Marlene , Voelkel Norbert , Habtezion Aida , Nicolls Mark 
Published: July 2021

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

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

In both PH models treatment resulted in development of PH with significantly higher RVSP and particular significantly pronounced RVH in female than in male in both SU5416 and CH groups (Fulton index: 0.41±0.01vs.0.33±0.02 and 0.52±0.03vs.0.37±0.01, p< 0.05). However, circulating estrogen levels were found to be significantly elevated in female than in male in all animal groups. For both female and male AT animals IR of Tregs prevented PH with RV remodeling, as well as decreased perivascular fibrosis and increased estrogen receptor (ER)β expression in lung and RV vascular wall.
In vitro studies on coculture of Tregs with RLMECs and RCMECs resulted in an upregulation of IL-10, HO-1, PDL1, ERα, ERβ, activation of pAKT pathway, and endothelial nitric oxide synthase (eNOS), which was abrogated with ER antagonist ICI182,780.
In addition, compared with control male AT rats, control female animals had increased expression of HO1, HO2 enzymes in lung and RV vascular wall endothelial/Reca+ cells as well as increased capillary density in RV. Thus, differential HO expression between the genders might account for the PH susceptibility.

Conclusions:
Our data suggest that Tregs signaling is required as a major mechanism with possible mutual interaction of endogenous estrogen to prevent endothelial injury related gender dimorphism for the development of PH.
Abstract 17582: Monitoring Novel Anticoagulants Dabigatron, Rivaroxaban and Apixaban Using Modified Thrombelastography
Authors: Artang Ramin , Galloway Gregg , Dalsgaard Nielsen Jorn 
Published: July 2021

Background:
Novel anticoagulants NOACS dabigatran DABI rivaroxaban RIVA and apixaban APIX do not require routine monitoring. There are situations where monitoring would be useful including bleedings, trauma, and thromboembolic events while on anticoagulation.

The aim of this in vivo study was to assess the anticoagulant effect of NOACS with novel modified TEG assay containing ecarin and factor Xa concentrate.

Methods:
9 healthy male volunteers were given single dose of oral DABI 150mg or RIVA 20mg or APIX 5mg and were phlebotomized at 0, 1 and 3 hours after intake of NOAC. Reaction time R was measured using TEG®5000. Concentrations (conc.) of DABI, RIVA and APIX were measured using chromogenic assay Biophen® DTI and DiXaI. Based on available literature on pharmacokinetics of NOACS, clinical range for each agent was estimated. The R values was correlated to the drug conc. and sensitivity SN, specificity SP, positive and negative predictive values (PPV&NPV) for the minimum therapeutic range of each agent was calculated.

Results:
Using Ecarin assay, R was highly correlated with DABI conc. r = 0.96, p < 0.0001. R value of >5.7 had 88% SN 100% SP, 100% PPV and 95% NPV for DABI conc. of >50ng/ml.

Using Factor Xa assay, R was highly correlated with RIVA conc. r = 0.89, p < 0.0001. R value of >4.8 had 94% SN, 100% SP, 100% PPV, and 92% NPV for RIVA conc. of >100ng/ml.
Using Factor Xa assay R was highly correlated with APIX conc. r = 0.86, p < 0.0001. R value of >4.3 had 93% SN, 100% SP, 100 PPV and 93% NPV for APIX conc. of >50ng/ml.

Conclusion:
We have for the first time demonstrated that TEG® point-of-care device can monitor the NOACS effect on the hemostasis with highly significant correlation with the drug levels of each agent. This novel technology is easy to use on whole blood without need for specialized expertise. Larger clinical studies are warranted for correlation of TEG findings and clinical outcome.
Abstract 17783: Improved Aortic Valve Area Calculation Using a Novel Biplane Echo Continuity Equation
Authors: Leucker Thorsten M , Shapiro Edward P 
Published: July 2021

The aim of this study was to improve the accuracy of transthoracic echo- cardiographic (TTE) assessment of the aortic valve area (AVA) in patients with aortic stenosis (AS).
The traditional continuity equation (CE) for determining AVA requires a measurement of left ventricular outflow tract (LVOT) area, which is calculated from a linear LVOT dimension using the parasternal long axis view, assuming circular geometry. However, routine use of multidetector computed tomography (MDCT) in patients undergoing evaluation for transcatheter aortic valve replacement (TAVR) has shown that the LVOT is elliptical rather than round. Assumption of circular geometry may introduce inaccuracies into AVA assessment.
A total of 61 patients (76 ± 11 years of age, 61% men) with isolated calcific AS (mean gradient 42 ± 9 mm Hg; ejection fraction 56 ± 11%) underwent Doppler TTE as part of pre TAVR or aortic valvuloplasty evaluation. AVA was calculated by TTE using two near- perpendicular planes (parasternal long axis and apical five chamber view) to evaluate the LVOT. A modified CE was used to calculate AVA (cm2) = (π((D1 x D2)/4)x LVOT VTI)/(AV VTI) in order to account for the elliptical rather than round shape of the LVOT. AVA measurements from the traditional and modified CE were compared to invasive AVA assessment.
Biplane (Figure, Panel B+D) vs. traditional single plane (Panel A+C) TTE measurement of the LVOT yielded a significantly improved positive correlation between TTE and invasive AVA assessment (r2=0.861 vs. 0.296) and a markedly reduced mean error (0.07 cm2 vs. 0.18 cm2), p<0.001.
Utilizing the proposed modified continuity equation greatly improves the accuracy of TTE guided AVA measurements. This simple calculation can be performed using standard TTE without additional costly equipment (ie, biplane transducers), without additional echo views (ie, more sonographer time), and without the need to subject patients to further invasive or non- invasive testing (ie, TEE or MDCT).
Abstract 18854: Long-term Follow-up After Percutaneous Left Atrial Appendage Ligation With the Lariat Device
Authors: Gianni Carola , Di Biase Luigi , Mohanty Sanghamitra , Trivedi Chintan , Gökoglan Yalçin , Günes Mahmut , Bai Rong , Burkhardt J D , Horton Rodney , Krumerman Andrew , Palma Eugene , Gibson Douglas , Price Matthew J , Valderrabano Miguel , Lakkireddy Dhanunjaya , Natale Andrea 
Published: July 2021

Introduction:
The objective of this retrospective multicenter study is to report the initial long-term performance results after percutaneous exclusion of the LAA with the endo-epicardial Lariat device to prevent AF-related thromboembolic events.

Methods and results:
Patients with successful LAA ligation and at least 1-year follow-up were analyzed (N=355). At 1 year, TEE follow-up was present in 172 patients. A leak was defined as presence of flow into the LAA as assessed by TEE.

At 6 months, 19 (11%) patients had a leak; 2 strokes occurred: 1 in a patient without a leak and 1 associated with mesenteric ischemia in a patient without a known acute leak, who died before repeat TEE could be performed.
At 12 months, 34 (20%) patients had a leak; 6 patients developed a neurological event (5 strokes and 1 TIA), 4 in patients with a leak, 2 in patients without a leak.
3% were followed-up for more than one 1 year (with a mean of 21±9 months). 1 additional thromboembolic event (TIA) occurred 14 months post-implant in a patient without anticoagulation and with a partially excluded LAA (stump), although no leak or thrombus were detected on standard TEE. Among patients with a leak (36% of those with long-term follow-up), 75% were on long-term anticoagulation and no additional TE events were detected.
Out of 355 patients, 9 (2.5%) patients had a neurological event: 4 with a leak, 4 without a leak and 1 in a patient where TEE was not repeated. Considering those with known LAA status, thromboembolic events were more common in patients with a leak (4/34 vs 4/136; RR 4, 95% CI 1.1-15.4).

Conclusion:
In this multicenter experience with the Lariat device, the rate of leaks was high (20% of those with TEE follow-up at 1 year). Thromboembolic events were not rare (overall, 2.5%), and occurred more frequently in patients with a leak (RR 4).
Abstract 18895: A Novel Gene Involved in Severe Neonatal Cardiomyopathy
Authors: Herkert Johanna C , Almomani Rowida , Verhagen Judith M , Wessels Marja W , Bertoli-Avella Aida M , van Slegtenhorst Marjon A , Verdijk Rob M , du Plessis Frederik A , Frohn-Mulder Ingrid M , Brosens Erwin , Hofstra Robert M , van Spaendonck-Zwarts Karin Y , Asimaki Angeliki , van der Zwaag Paul A , van der Smagt Jasper J , Timmer Bert , van Stuijvenberg Margriet , Sinke Richard J , van Tintelen J. Peter , van de Laar Ingrid M , Jongbloed Jan D 
Published: July 2021

Cardiomyopathies (CMP) in children are heterogeneous disorders of cardiac muscle with a relatively high incidence in infancy (8/100.000) as compared to older children (0.7/100.000). Beyond infancy, CMP is the most important indication for heart transplantation and transplantation free survival at 5 years after initial diagnosis is only 54%.
Mutations in over 65 genes encoding sarcomeric, cytoskeletal and calcium-metabolizing proteins, cell-signaling molecules, and mitochondrial enzymes have been shown to cause CMPs. This has led to new recommendations for diagnostic evaluation and family screening incorporating genetic testing. However, present (targeted/custom based) diagnostic tests do not represent the whole spectrum of genetic etiologies and are leading to a correct diagnosis in just a subset of pediatric CMP patients.
We present four children from two consanguineous families of Dutch and Moroccan descent with severe neonatal onset of CMP, ranging from lethal cardiomegaly with reduced contractility in three to severe left ventricular hypertrophy that remained stable in one child.
A combined approach using homozygosity mapping and exome sequencing in both families identified a homozygous splice site variant resulting in exon skipping in the Dutch family, and a homozygous nonsense mutation in the Moroccan family within the same gene. This novel disease causing gene is implicated in the early differentiation of cardiomyocytes. Both variants were confirmed with Sanger sequencing and absent in large control populations. Previously published studies in a knockout mouse model demonstrated the functional role of this gene in CMPs. Additionally, we investigated the effect of the homozygous splice site mutation on the expression of different proteins at myocardial cell-cell junctions and myofibrils. These results point towards a role in intercalated disk remodeling. Electron microscopy- and protein expression studies on heart tissue of the patients are ongoing.
Our findings add a new autosomal recessive gene to the list of genes already implicated in pediatric CMP, underscoring its genetic heterogeneity. Furthermore, our study indicates that the application of exome sequencing can improve the diagnostic yield in pediatric CMP.
Abstract 19161: cAMP Regulated Transcriptional Coactivator 1 - A Novel Player in Cardiac Hypertrophy
Authors: Morhenn Karoline M , Quentin Thomas , Schroeder Sabine , Pahl Anja , Steinmetz Michael , Geertz Birgit , Eschenhagen Thomas , Schlossarek Saskia , Carrier Lucie , Cardinaux Jean-René , Zimmermann Wolfram-Hubertus , Lutz Susanne , Oetjen Elke 
Published: July 2021

Maladaptive cardiac hypertrophy leads to heart failure, a common cause for hospitalization. Chronic β-adrenergic, PKA dependent signaling and calcineurin contribute to hypertrophy. These signals converge in many tissues on the cAMP Regulated Transcriptional Coactivator 1 (CRTC1).
We studied if CRTC1 promotes the development of maladaptive cardiac hypertrophy in human and murine hearts.

In cardiomyocytes, treatment with β-adrenoceptor agonist isoprenaline dephosphorylated, thus activated 59 ± 5 % of total CRTC1, as seen by immunoblot (n = 3-4). Activation was prevented by propranolol. CRTC1 was not activated by endothelin or angiotensin II. CRTC1 protein content was enhanced in human and murine heart tissue under conditions of acquired and inherited maladaptive hypertrophy, seen by immunoblot (n = 7-8).
Crtc1
-deficient mice (KO) showed a higher ratio of heart weight to tibia length than their wild-type littermates (WT) (8.6 ± 0.4 mg/mm vs. 10.9 ± 0.8 mg/mm in WT and KO, respectively, n = 12) and increased myocyte size (516 ± 8 μm
2
vs. 590 ± 11 μm
2
in WT and KO, respectively, n = 3 hearts). Echocardiographically assessed, the ejection fraction, fractional area shortening and cardiac output were reduced by 47 ± 8 %, 49 ± 12 % and 42 ± 9 %, respectively, in KO mice (n = 6-9). mRNA levels of
Nppa
,
Nppb
,
Acta1
,
Myh7
and the pro-fibrotic
Ctgf
did not differ between WT and KO mice (n = 12-15). By reducing G
αq
-protein induced signals in the heart, the Regulator of G-Protein Signaling 2 (RGS2) reduces hypertrophy. In KO mice the
Rgs2
mRNA and protein levels were reduced by 26 ± 10 % and by 38 ± 8 %, respectively (n = 8-10). In a luciferase reporter gene assay overexpression of CRTC1 stimulated
Rgs2
promoter transcriptional activity 1.8 fold (± 0.1); mutation of the CRTC1-interaction site, the cAMP-response element, prevented CRTC1-induced transcriptional activity (n = 6). In addition, chromatin immunoprecipitation showed the recruitment of endogenous CRTC1 to the
Rgs2
promoter in cardiac tissue.

In conclusion, our data indicate that increased CRTC1 protein content in maladaptive cardiac hypertrophy is a compensatory mechanism to delay disease progression, in part by upregulation of RGS2. Thus, CRTC1 represents a novel player of cardiac hypertrophy.