bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14616: Tailored Low Voltage Zones Ablation Using Contact Force Sensing Technology in Patients With Persistent Atrial Fibrillation (TWEET-AF): A Pilot Study
Authors: DAmbrosio Gabriele , Raffa Santi , Romano Silvio , Frommhold Markus , Alothman Obaida , Borisov Georgi , Issa Karam , Penco Maria , Geller Christoph
Published: November 2020

Introduction:
Although pulmonary vein (PV) isolation (PVI) is very effective in paroxysmal atrial fibrillation (AF), in patients (pts) with persistent AF, PVI often is not sufficient. Many studies suggested that low voltage zones (LVZs) outside of the PV might be involved in the complex mechanisms perpetuating AF. However ablation strategies involving substrate modification (SM) did not show additional benefits in persistent AF pts. Those studies were performed before the introduction of contact force technology, and the most likely explanation for these results could be the inability to achieve effective transmural lesions and continuous linear ablation.

Hypothesis:
We hypothesized that the use of contact force technology would improve ablation efficacy. Therefore, we analyzed the long-term outcome after two different ablation strategies in pts with persistent AF depending on whether there was evidence of LVZs in the left atrium or not.

Methods:
The presence of LVZs were defined as sites of >3 adjacent low-voltage points <0.5 mV during electrophysiology study. Depending on the location of the LVZ, linear ablation was performed. Catheter ablation was performed using TactiCath™ or SmartTouch™ ablation catheters aiming at contact values ≥10g <20g and FTI >400g/s. Ablation was performed in a temperature-controlled fashion with energy of 30W except at the posterior wall (20-25W).

Results:
121 consecutive pts with persistent AF (46 female, median age 66 [59-72] years, mean duration of AF 16 [7-73] months, CT derived LA volume index 66 [56-75]ml/m2) were included: pts without LVZs underwent PVI alone (n = 74), in pts with LVZs, PVI + SM (n = 47) was performed (mitral Isthmus line in 2, supero-septal line in 39, and roof line in 47; bidirectional block was achieved in 100%, 97%, and 100%, respectively). After a median follow-up of 13 [6-21] months, 86% of pts without and 78% with substrate were in sinus rhythm, mainly without antiarrhythmic drugs (89% PVI only, 84% PVI + SM).

Conclusions:
In patients with persistent AF without LVZs, PVI alone leads to excellent 2-year freedom from AF. In pts with LVZs, additional substrate modification with CF sensing technology is associated with improved success rates compared to previous studies.
Abstract 14900: Human Atrial Fibrillation Drivers Revealed by Machine Learning Using Multicomponent Electrograms and 3D CE-MRI Structural Features
Authors: Mikhailov Aleksei , Hansen Brian , Fazio Matthew , Zakharkin Stanislav , Zhao Jichao , Nalar Aaqel , Kennelly James , Subr Megan , Rodrigo Miguel , LI Ning , Uma Mylavarapu , Kalyanasundaram Anuradha , Buck Benjamin , Janssen Paul M , Mohler Peter J , Whitson Bryan , Mokadam Nahush , Hummel John , Fedorov Vadim V
Published: November 2020

Introduction:
Conventional multielectrode mapping is not sufficient to reveal subsurface intramural activation. Thus, atrial fibrillation (AF) driver identification remains challenging. To overcome these limitations we utilized machine learning (ML) to identify AF drivers based on the combination of electrogram (EGM) and 3D structural magnetic resonance imaging (MRI) features.

Hypothesis:
Detailed electrogram features analysis, including minor deflections, combined with local structural features, can be used to define AF driver.

Methods:
Sustained AF was mapped in coronary perfused explanted human atria (n=7) with near-infrared optical mapping (NIOM) (0.3-0.9mm
2
resolution) and 64-electrode mapping catheter (3mm
2
resolution). Unipolar EGMs were analyzed for multiple features of the steepest negative deflection and the 2nd-4th steepest deflections in multicomponent EGMs. Atria underwent 9.4T MRI (154-180μm
3
resolution) with gadolinium enhancement and histology validation of fibrosis. Both 3D structural and EGM data from NIOM defined driver and non-driver regions were processed by ML algorithms (LR; PLSDA; GBM; CRF; PSVM; RSVM) using double cross-validation.

Results:
AF drivers’ reentrant tracks were defined by NIOM activation mapping, the gold-standard, and confirmed by targeted ablation. The best performing ML algorithm (PLSDA) correctly classified mapped driver region with 76.1% accuracy on the testing data. The most important features included sub-endocardial fibrosis, sub-epicardial fiber orientation, local wall thickness, beat-to-beat variability of multicomponent EGM deflections.

Conclusions:
The ML models pre-trained on combined EGM and structural features allow efficient classification of AF driver vs non-driver regions defined by the NIOM gold-standard. The results suggest that AF driver substrates formed by the combination of 3D fibrotic structural features, which correlate with local EGM characteristics.
Abstract 14908: Anatomic Validation of Induced Pluripotent Stem Cell-derived Aortic Smooth Muscle Cell Model of Loeys Dietz Syndrome
Authors: Pedroza Albert J , Churovich Samantha , Yokoyama Nobu , Nakamura Ken , Iosef Husted Cristiana , Fischbein Michael P
Published: November 2020

Introduction:
Mutations in TGF-beta (TGF-ß) signaling genes lead to aortic root aneurysm in Loeys Dietz syndrome (LDS). Smooth muscle cells (SMCs) in the proximal aorta develop from two embryologic origins: second heart field (SHF) and neural crest (NC). Induced pluripotent stem cell (iPSC) models simulate these lineages, but direct correlation to clinical disease is lacking.

Hypothesis:
iPSC-derived SMCs accurately model lineage-specific aortopathy in LDS.

Methods:
We generated SMC lines from root and ascending aortic surgical tissue and iPSC-derived SMCs through SHF and NC-specific pathways from an LDS patient (
TGFBR1
mutation). Lineage-specific TGF-ß responses were determined by western blot/ELISA. RNA sequencing and RT-PCR identified SMC transcriptomes.

Results:
Aortic root SMCs showed greater canonical TGF-ß activation (p-SMAD2/3) versus ascending at baseline and with TGF-ß stimulation (
Figure
). Synonymous results were seen in SHF versus NC SMCs from the iPSC pathway. RNAseq identified 1,600 differentially expressed genes between iPSC lineages, including altered TGF-ß receptor and ligand expression profiles. Primary aortic lines validated iPSC data: root SMCs showed enriched TGF-ß receptor 1/2/3 expression (1.7-, 3.9- and 5.9-fold) while ascending SMCs overexpressed TGFB1 and TGFB2 ligands (1.8- and 3.5-fold). Despite discordant TGF-ß activation, SMC contractile gene expression was similar between lineages in aortic and iPSC-SMCs, suggesting alternative downstream effects in LDS aneurysm.

Conclusion:
iPSC-derived SMCs effectively model lineage-specific aortic root aneurysm pathology, validating this model as a tool for mechanistic testing and therapy discovery.
Abstract 14910: Role of 3.3fr Mapping Catheters in Defining and Ablating Mechanisms of Ventricular Arrhythmias: A Multicenter Experience
Authors: Rogers Albert J , Greif Shana , Perino Alexander C , Shah Rajan L , Viswanathan Mohan N , Tholakanahalli Venkatakrishna N , Singh David , Badhwar Nitish
Published: November 2020

Introduction:
Ventricular arrhythmia (VA) mechanisms arising from the crux, summit, and epicardium are often not accessible from the endocardium. The 3.3Fr multipolar mapping catheters (3FMC) (Map-iT, Access Point Technologies, Rogers, MN) can be used to map deep within the coronary sinus (CS) branches and other locations difficult to access with standard catheters.

Objective:
We present a case series of and techniques for VA ablations guided by the 3FMC.

Methods:
We retrospectively reviewed VA ablations at 3 centers to describe the utility of the 3FMC in diagnosis and ablation of the arrhythmia.

Results:
We reviewed 33 patients who underwent VA ablations guided by the 3FMC. Patients (age 59.0 ± 15.4 years, 72% male, LVEF 41.5 ± 10.3%, 93% non-ischemic) had ventricular tachycardia (32%) or high-burden PVCs (68%). The 3FMC was used to interrogate the epicardium via the coronary sinus branches allowing interrogation of the LV crux (Fig. A) and LV summit (Fig. B). Early potentials in the poster-septal branch of CS guided alcohol ablation to focal site in septum not reachable by traditional catheters. Continuous signal on the 3FMC in the posterolateral branch of CS elucidated microreentry and guided more extensive epicardial ablation. Overall, the 3FMC measured signals 18.7 ± 11.3ms early and diagnosed 75% focal, 10% micro-reentrant, and 15% macro-reentrant VAs. Ablation was successful in 76% of cases.

Conclusions:
High definition mapping with the 3FMC allows diagnosis of VA mechanisms in locations not easily reachable by traditional catheters. Improved mapping of the CS branches enables interrogation and ablation planning of epicardial, summit, and crux VAs and may increase the likelihood of successful VA ablation.
Abstract 14919: Myocardial T
1
Mapping for Prediction of Left Ventricular Reverse Remodeling in Patients With Recent-onset Dilated Cardiomyopathy: a Comparison With Histological Tissue Characterization
Authors: Ishiura Junko , Nakamori Shiro , Imanaka-yoshida Kyoko , Hiroe Michiaki , Nakata Kei , Ishida Masaki , Moriwaki Keishi , Fujimoto Naoki , Sakuma Hajime , Dohi Kaoru
Published: November 2020

Background:
Accurate prediction of left ventricular reverse remodeling (LVRR) in dilated cardiomyopathy (DCM) remains challenging. The purpose of this study is to assess the potential of cardiovascular magnetic resonance (CMR) T
1
mapping to predict LVRR by histological confirmation.

Methods:
Twenty-one DCM patients (12 male, mean age 49 ± 13 years) underwent cine, late gadolinium enhancement (LGE) CMR, and triple-slice T
1
mapping using a modified Look-Locker inversion recovery sequence at 3T before receiving optimal medical therapy. LVRR was defined as an absolute increase in LV ejection fraction (LVEF) from ≥10% to a final value of >35%, accompanied by a decrease in LV end-diastolic volume (LVEDV) ≧10% at midterm (mean time 18 months) CMR follow-up. Extra-cellular volume (ECV) was quantified from pre and post-contrast T
1
values of the blood and myocardium with hematocrit correction. Biopsy samples were used for quantification of collagen volume fraction (CVF).

Results:
LVRR was observed in 11 patients (52%). The mean native T
1
, ECV, and histological CVF were 1395 ± 49 ms, 0.33 ± 0.03, 0.13 ± 0.04, respectively. Native T
1
yielded comparable ability to ECV measurements for detecting histological CVF (r=0.49, 0.52, both p <0.05). While 14 patients (67%) showed focal scar on LGE, there was no significant difference in histological CVF between patients with and without focal scarring (p=0.6). Native T
1,
but not ECV and CVF, correlated well with absolute LVEF increase and relative percent decrease of LVEDV and LV end-systolic volume (r=-0.55, 0.55, 0.56, all p <0.05). Native T
1
<1400 ms provided 90% sensitivity and 82% specificity, with the C-statistic of 0.86 (95% CI 0.64-0.97), for predicting LVRR. On the other hand, the C-statistic of ECV, LGE and histological CVF were 0.72 (95% CI 0.48-0.89), 0.53 (95% CI 0.31-0.75) and 0.66 (95% CI 0.43-0.85), respectively.

Conclusions:
Myocardial native T
1
have the potential to predict LVRR beyond LGE and histological assessment.
Abstract 14930: Involvement of Chloride Channel (clic) in Myocardial Fibrosis of Pressure-overload Model Mice and Dilated Cardiomyopathy Patients
Authors: Oguri Gaku , Nakajima Toshiaki , Seitaro Nomura , Takahumi Nakajima , Kikuchi Hironobu , Obi Syotaro , Inoue Teruo , Issei Komuro
Published: November 2020

Introduction:
Pressure overload induces cardiac hypertrophy, electrical remodeling due to changes in various channels, and eventually leads to fibrosis, hardening of the heart, left ventricular diastolic dysfunction, and heart failure. Chloride channels (chloride intracellular channels, Clic) are localized in both plasma membranes and intracellular organelles of various cells, and have recently been reported to be associated with atrial fibrosis. In this study, we examined single-cell RNA-seq analysis of cardiomyocytes for changes in Clic using a pressure overload model due to transverse aortic coarctation (TAC). In addition, a similar analysis was performed on ventricular myocytes in dilated cardiomyopathy.

Methods:
Single ventricular myocytes were collected from the free wall of the left ventricle after TAC by collagenase treatment in the cardiac hypertrophy phase (3 days after TAC, 1 or 2 weeks (W)) and the heart failure phase (4,8W). The expression of various genes in ventricular myocytes was analyzed for single cells by RNA-seq and compared with sham mice. In addition, a similar study was performed from single ventricular myocytes obtained from dilated cardiomyopathy patients and donors.

Results:
The expression of myosin heavy chain β (Myh7), a fetal gene, was increased by pressure overload, but the expression of BNP and ANP genes was increased along with the expression of adult Myh6. Regarding Clic, Clic1,4 and 5 increased as compared with Sham mice. Clic1, Clic1 and 4 increased from 3d, and at 8W, Clic1, 4, and 5 also increased . The expression level of these Clic genes is associated with the genes associated with fibrosis (Col4a1, 4a2, 6a2, connective tissue growth factor (CTGF), transforming growth factor-beta 2 (TGFβ2). The KEGG pathway analysis using DAVID for genes with significant associations with Clic1,4, and 5 revealed a strong association with activation of Focal adhesion pathway. Single cell RNA-seq analysis of single ventricular myocytes from patients with dilated cardiomyopathy also showed a increase in CLIC4 and 5 genes compared to healthy donors.

Conclusions:
Single cell RNA of ventricular myocytes -seq analysis revealed the involvement of chloride channel Clic in myocardial fibrosis and structural remodeling in failing hearts.
Abstract 14931: Low-Dose Prasugrel Has Prognostic Superiority to Clopidogrel in High-Bleeding Risk Patients Undergoing Contemporary Percutaneous Coronary Intervention
Authors: Abe Takuro , Jujo Kentaro , Hata Takehiro , KAMISHIMA KAZUHO , Koganei Hiroshi , Sakamoto Tomohiro , Yamaguchi Junichi , Hagiwara Nobuhisa
Published: November 2020

Introduction:
The combination of aspirin and P2Y12 receptor antagonist is the standard antiplatelet therapy after percutaneous coronary intervention (PCI). Previous trials reported that prasugrel reduced the risk of ischemic events, but increased bleeding events compared to clopidogrel.

Hypothesis:
The prognostic impact of low-dose prasugrel (3.75 mg/day), which the dose was determined by phase II trial, is different from that of clopidogrel, depending on patient’s bleeding risk.

Methods:
This study is a subanalysis from the TWINCRE registry that is a multicentral prospective cohort including patients who underwent PCI. We analyzed 1,001 patients who received the combination of aspirin and prasugrel or clopidogrel after PCI. The primary endpoint was a composite of major bleeding event and major adverse cardiovascular and cerebrovascular events (MACCE) including any death, acute coronary syndrome, stent thrombosis, stroke and heart failure hospitalization.

Results:
There were 490 patients with high bleeding risk (HBR) and 511 patients with low bleeding risk (LBR), based on ARC-HBR criteria. In HBR patients, the Low-dose prasugrel group had significantly lower rates of MACCE (Log-rank, p=0.003) and the composite endpoint than the Clopidogrel group (p=0.001). While, in LBR patients, there was no significant difference in rates of MACCE or the composite endpoint between the groups (p=0.76, p=0.15, respectively), and a higher rate of major bleeding event in the Low-dose prasugrel group (p=0.002). With Cox proportional hazards analysis, low-dose prasugrel has still retained the superiority to clopidogrel regarding with the composite endpoint in HBR patients, even after adjusting with diverse covariates (hazard ratio: 0.33, 95% confidence interval: 0.16-0.65).

Conclusion:
In the multicenter cohort study in Japan, low-dose prasugrel showed a long-term prognostic superiority to clopidogrel only in HBR patients undergoing contemporary PCI.
Abstract 14938: Impact of Cerebrovascular Comorbidity on Prognosis in Patients Undergoing Percutaneous Coronary Intervention: 1-year Data From Japanese Multi-center Registry
Authors: Ahmed Khlood
Published: November 2020

Background:
Cardiovascular and cerebrovascular diseases are considered the principal cause of morbidity and mortality worldwide; the effect of stroke-induced cardiac manifestations is well recognized; however, not enough clinical data has been found about the impact of stroke with underlying cardiac disease. This study’s objective is to assess the impact of stroke on the prognosis of patients with underlying IHD, who underwent PCI treatment.

Methods and Results:
This was a multicenter, 1-year observational study in patients undergoing PCI in one of the 17 participating centers across japan. 18,495 patients were registered on the PCI list; 2481 patients had a prior stroke experience, whereas 15979 were stroke-free. Our study revealed that stroke patients were significantly older (mean age73.5±9.6, 69.7(±11.5) respectively), and suffered from more comorbidities (diabetes, hypertension, and chronic kidney disease, p<0.0001). During the one-year period, subjects with stroke showed higher incidence of clinical events compared to those without stroke; to illustrate, all-cause death accounted for 6.2% in patients with stroke, in contrast to only 2.8% in stroke-free patients (p<0.0001),cardiac death amounted for 2.2% and 1.2% respectively (P<0.0001), recurrent stroke for 3.1% and 1.2% (P<0.0001), non-cardiac death for 3.6% and 1.54% (P<0.0001),and finally, hemorrhagic complications with 2.6% and 1.3% (p<0.0001).Kaplan-Meier analysis revealed that stroke patients had a higher probability of all-cause mortality, cardiac death, and recurrent stroke (log-rank p<0.0001). Cox hazard analysis also revealed that the presence of stroke is a significant indicator in determining the outcome of cardiac death (HR=1.457, 95%CI=1.036–2.051, p=0.031), thus proving it to be a crucial predictor on cardiac prognosis.

Conclusion:
History of prior stroke was common in PCI patients, and independently associated with a higher rate of subsequent cardiovascular and cerebrovascular events recurrence, thus highlighting urgent need for comprehensive prevention of cardiac and cerebrovascular diseases
Abstract 14948: Comparative Effectiveness of CRT in Older Patients With Heart Failure: Systematic Review and Meta-Analysis
Authors: Juggan Saeed , Reilly Clifford A , Ponnamreddy Praveen K , Gilstrap Lauren , Zeitler Emily
Published: November 2020

Background:
The pivotal cardiac resynchronization therapy (CRT) trials enrolled patients significantly younger than the typical contemporary heart failure with reduced ejection fraction (HFrEF) patients. Benefits of CRT in older HFrEF patients is largely unknown and may be less due to higher comorbidity burdens and higher procedural risk. We sought to address this evidentiary gap through meta-analysis.

Hypothesis:
Compared to patients <70 years old (”younger”), patients ≥ 70 years old (“older”) have similar mortality rates, rates of complications and changes in ejection fraction (EF) following CRT.

Methods:
PubMed, The Cochrane Library, Scopus, and Web of Science were queried for comparative effectiveness studies of CRT in older HFrEF patients. Differences in mortality and mean difference (MD) in EF were calculated between groups. Random effects meta-analysis of MD in EF (older minus younger) and relative risk (RR) of death and complications are reported along with estimates of heterogeneity.

Results:
Seven studies [n= 4381 younger, 1203 older] were included in LVEF meta-analysis. Compared to younger patients, there was greater EF improvement in older patients [MD 1.20; 95% CI 0.13 - 2.28, p=0.03, I
2
=46%]. RR of mortality was analyzed for 11 studies [n=5038 younger, 1653 older] (Figure). Survival was better in younger patients [RR 1.06; 95% CI 1.04 - 1.09, p<0.01, I
2
=0%]. No significant differences in complication rates were observed between younger and older patients.

Conclusions:
CRT in older patients was associated with greater improvement in EF than younger patients. Mortality is greater in older patients which may reflect greater underlying risk of death from competing causes.

Figures:
Abstract 14959: Effect of Empagliflozin on Total Events of Myocardial Infarctions by Subtype in the EMPA-REG OUTCOME Trial
Authors: Fitchett David H , Zinman Bernard , Inzucchi Silvio E , Wanner Christoph , Anker Stefan D , Pocock Stuart , Kaspers Stefan , George Jyothis T , Johansen Odd Erik , Jamal Waheed , Mattheus Michaela , Vedin Ola , Hantel Stefan , Lund Søren S
Published: November 2020

Introduction:
In EMPA-REG OUTCOME®, the sodium-glucose transporter inhibitor, empagliflozin (EMPA), reduced the risk of first cardiovascular (CV) events primarily CV mortality and hospitalization for heart failure in patients with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease. In analyses including total events, EMPA also reduced the risk of myocardial infarction (MI). Here we report the effects of EMPA on the total number of MIs by subtype.

Methods:
Patients were randomized to receive EMPA 10 mg, EMPA 25 mg, or placebo. We assessed the effect of pooled EMPA versus placebo on total (first plus recurrent) events of fatal and non-fatal MI using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events.
Post-hoc,
we analyzed established subtypes of MI: Type 1: Typically related to plaque-rupture or thrombus; Type 2: Supply-demand; Type 3: Sudden-death related (i.e., fatal MI); Type 4: Percutaneous coronary intervention related; and Type 5: Coronary artery bypass graft related. Except type 3 MIs, MIs were non-fatal. The MIs, including subtypes, were centrally adjudicated and could be assigned to more than one subtype.

Results:
7,020 patients were treated. Overall, there was 421 total events of MIs. Specifically, 299, 86, 26, 19, and 1 of the MIs were classified as type 1, 2, 3, 4, and 5 MIs, respectively (not mutually exclusive). Overall, EMPA reduced the risk of total events of MI by 21% versus placebo (rate ratio [95% CI], EMPA versus placebo: 0.79 [0.620; 0.998], p=0.0486; each MI only counted once). The overall reduction in total events of MIs by EMPA was driven by the effect on type 1 and 2 MIs, as well as type 3 MIs, with limited number of type 4 and 5 MIs (Figure).

Conclusions:
EMPA reduced the risk of total MI events with consistent effects across the most common etiologies, the type 1 (plaque-rupture or thrombus) and 2 (supply-demand) MIs.
Abstract 14962: Empagliflozin’s Cardiovascular Impact in High-Risk Patients With Type 2 Diabetes and Obstructive Pulmonary Disease: An Inquiry From EMPA-REG OUTCOME
Authors: Anker Stefan D , Fitchett David H , Zinman Bernard , Ofstad Anne Pernille , Wanner Christoph , Vedin Ola , Schinzel Birgit , Yaggi Henry K , George Jyothis T , Sander Leif Erik , Inzucchi Silvio E , Verma Subodh
Published: November 2020

Introduction:
Type 2 diabetes (T2D) and chronic obstructive pulmonary disease (COPD) often co-exist yielding increased risk of cardiovascular (CV) complications, including heart failure (HF). In the EMPA-REG OUTCOME trial, empagliflozin (EMPA) reduced the risk of CV death and hospitalization for HF (HHF) in patients with T2D and CV disease (CVD). We hypothesized that patients with COPD had a higher risk of CV outcomes than those without COPD, but similar treatment benefits on CV outcomes from EMPA as the overall population.

Methods:
In total, 7020 patients were treated with EMPA 10mg, 25mg, or placebo (PBO) with median follow-up of 3.1 years. We defined COPD at baseline (BL) by investigator reported presence of COPD or emphysema, or the use of medications for obstructive airways disease. We explored the effect of pooled EMPA groups vs. PBO within the subgroups of patients with vs. without COPD on CV death, HHF, HHF or CV death (excluding fatal stroke), all-cause death and 3-point-MACE by Cox regression adjusted for baseline risk factors.

Results:
The 707 (10.1%) patients with COPD at BL were slightly older (65±8 vs. 63±9 yrs), had more often HF at BL (17 vs. 9%) and coronary artery disease (84 vs. 75%), used insulin (56 vs. 47%) and diuretics (57 vs. 42%,) more frequently, but had similar beta-blocker use (64 vs. 65%) as compared to those without COPD. During follow-up, those with COPD in the placebo group had increased risk of HHF (HR 2.15 [95%CI 1.32-3.49], p=0.002), HHF or CV death (HR 1.60 [1.10-2.33], p<0.015), and all-cause death (HR 1.60 [1.09-2.35], p<0.02). EMPA consistently reduced all CV outcomes irrespective of COPD status (Fig).

Conclusions:
In EMPA-REG OUTCOME, 10% of patients had concomitant COPD. COPD patients were at increased risk of HHF, HHF or CV death, as well as all-cause death. EMPA consistently reduced these outcomes vs PBO among patients with and without COPD. These data suggest that EMPA’s benefits in patients with T2D and CVD are not attenuated by presence of COPD.
Abstract 14968: Geographic Variation in the Early Diffusion and of Sacubitril/Valsartan
Authors: King Ashleigh , Austin Andrea , Tomlin Stephanie , Gilstrap Lauren
Published: November 2020

Introduction:
In the PARADIGM-HF trial, sacubitril/valsartan demonstrated a 20% reduction in mortality and heart failure (HF) hospitalization compared to enalapril. Despite this success, diffusion has been slower than anticipated. To date, high co-payments have been identified as a key barrier. The aim of this study is to examine the role of geographic prescribing patterns in the early diffusion of sacubitril/valsartan, after controlling for cost.

Hypothesis:
There will be significant geographic variation in the use of sacubitril/valsartan, after controlling for cost.

Methods:
We used 100% Medicare Parts A and B and a random 40% sample of Part D to create a cohort of beneficiaries with heart failure with reduced ejection fraction (HFrEF) between 2016 and 2018. We calculated age, sex, race adjusted rates of sacubitril/valsartan use by hospital referral region (HRR) and used multivariable logistic regression to determine the association between geographic region and sacubitril/valsartan use, controlling for cost.

Results:
Early use rates of sacubitril/valsartan have been low: 1.9% in 2016, 3.3% in 2017 and 4% in 2018. There has been substantial geographic variation with most concentrated in the South and Northeast (
Figure
). After controlling for cost, HFrEF patients in the Northeast were 1.32 times (95% CI 1.26-1.29, p<0.001)) more likely, those in the South were 1.24 times more likely (95% CI 1.20-1.29, p<0.001)) and those in the West were 1.10 times more likely (95% CI 1.05-1.15, p<0.001) to receive sacubitril/valsartan compared to HFrEF patients in the Midwest.

Conclusions:
There has been substantial variation in the early diffusion of sacubitril/valsartan. In addition to cost, geographic prescribing patterns play a major role in early drug diffusion.
Abstract 14981: Altered Gene Expression in Diabetic Heart Failure Patients
Authors: Dhar Kajari , Qiu Fang , Zolty Daniel , Basma Hesham , Um John , Anderson Daniel R , Lowes Brian D
Published: November 2020

Introduction:
Diabetes and heart failure are very closely associated. Diabetes patients have an increased risk of developing heart failure and heart failure patients are at higher risk of developing diabetes. Changes occur in myocardial glucose metabolism in end stage heart failure patients and newer therapies for diabetes such as SGLTi improve heart failure outcomes. Our objective was to identify transcriptional changes associated with diabetes in heart failure patients.

Methods:
Transcriptional profiles were compared in heart tissues obtained at the time of LVAD implant among diabetic heart failure (HF) (n=16), non-diabetic (n=10) HF patients and control (n=3) non failing hearts. RNASeq analysis utilized a custom-targeted panel for 140 genes on the Ion Torrent Personal Genome Machine. Coverage analysis as well as mapping the reads and alignment was done using the Ion Torrent Browser SuiteTM. The Bejamini-Hochberg method was used to control the false discovery rate to be no more than 0.05. Ingenuity Pathway Analysis (IPA) was also performed to understand the biological pathways involved.

Results:
Our sample population was 82% male with an average age of 51 and 84% Caucasian, 14% African American and 2% Asian. Average ejection fraction was quite low <25% and average NYHA was 3.5 in the HF populations. Expressions of contractile muscle and ion channels proteins decreased significantly between HF patients and control. Increased expression of chemokine ligand 4 (CCL4), chemokine ligand 2 (CCL2) and collagen type 1 alpha1 (COL1A1) were observed in diabetic HF compared to non-diabetic HF patients. IPA analysis with log fold change between HF and control revealed activation of both methylation genes DNMT3A and B, necrosis of cardiac muscle and death of cardiomyocytes with 2.0 Z score.

Conclusions:
Diabetic heart failure patients have increased expression of chemokines and extracellular matrix genes, which may contribute to disease progression. Up regulation of CCL4 and CCL2 in diabetic HF patients may cause additional risk of heart diseases through inflammatory pathways and increased expression of collagen may contribute to myocardial fibrosis. Down regulation of contractile proteins, and ion channels were similar in diabetic and non-diabetic HF patients.
Abstract 14990: Pulmonary Vein Stenosis After Epicardial Atrial Fibrillation Ablation and Epicardial Left Atrial Appendage Occlusion: A Diagnostic Dilemma and Challenges in Management
Authors: Mohammed Moghniuddin , Apte Nachiket , Ansari Mohammed , Noheria Amit , Sheldon Seth , Reddy Madhu
Published: November 2020

Background:
Pulmonary vein stenosis is a dreaded complication of endocardial atrial fibrillation (AF) ablation but rare after epicardial ablation and has not been reported after epicardial left atrial appendage occlusion (LAAO).

Case:
A 55-year-old male was referred to our tertiary hospital for management of left superior pulmonary vein (LSPV) stenosis causing dyspnea on exertion. About 2 years prior to presentation, he underwent quadruple coronary artery bypass grafting for non-ST elevation myocardial infarction along with modified Cox-Maze procedure with pulmonary vein and posterior wall isolation as well as epicardial LAAO with AtriClip for history of paroxysmal AF. At our institute, V/Q scan showed ventilation-perfusion mismatch and absent perfusion of the left upper lobe (Figure 1A). Cardiac CT showed persistent LSPV occlusion (Figure 1B). TEE showed atrial appendage occluded with a clip and no flow was observed from LSPV (Figure 1C). After multidisciplinary discussion between cardiology and cardiothoracic surgery teams, surgical approach to remove the AtriClip was deemed futile as it was placed 2 years ago and less likely to result in resolution of stenosis. Thus, an endovascular approach was attempted with left atrial and pulmonary vein angiography showing LSPV to be 100% occluded (Figure 1D). Pulmonary vein recanalization was attempted but was not successful.

Conclusion:
Our case highlights the importance of recognition of PVS as a possible complication after epicardial LAAO as early intervention can improve patient outcomes. PVS has been previously described with Maze procedure but that patient was successfully treated with catheter-balloon angioplasty. Given 100% occlusion and difficulty with recanalization makes epicardial ablation a less likely cause of occlusion in our case. More careful application of Atriclip protocols might be necessary to prevent this potential complication.
Abstract 15013: Ischemic Mitral Regurgitation is Associated With Impaired Transforming Growth Factor/Bone Morphogenic Protein Signaling and Increased CD45+ Cell Presence in the Mitral Valve Interstitial Cell Population
Authors: Castillero Estibaliz , Howsmon Daniel P , Rego Bruno V , Xue Yingfei , Gorman Robert C , Sacks Michael , LEVY Robert , Ferrari Giovanni
Published: November 2020

Introduction:
Ischemic mitral regurgitation (IMR) develops in a fraction of patients in response to left ventricular (LV) remodeling after ischemia. IMR independently predicts adverse events and doubles mortality. While largely driven by LV distortion, the susceptibility of the mitral valve (MV) to undergo remodeling may play a role in determining whether MR develops. We hypothesized that impaired cellular response in MV cells may contribute to MR development by inducing maladaptive tissue remodeling.

Methods:
Dorsett hybrid sheep (n=32) were subjected to ligation of the circumflex coronary artery to induce myocardial infarction (MI). Development of MR was reported by echocardiography. MV leaflets and isolated MV interstitial cells (MVIC) were collected at baseline (Control), 4-, and 8-weeks post MI. RNAseq (150 paired end reads, 20 million reads/sample) was performed on MV leaflets from all groups. MVICs were treated with for 24h with 10ng/ml TGFβ1 of 50ng/ml BMP4.

Results:
Gene set enrichment analysis using pre-defined gene sets from the Gene Ontology project, considering genes with significant changes (p<0.05) between MV with/without MR showed enrichment of cardiac contraction biological processes. TGFβ/BMP-dependent SMAD7 was the main hub in the protein-protein-interaction network of the top contributing genes to the enriched pathways in MR.
In vitro,
collagen matrix-contracting ability of MR MVICs was higher than non-MR MI MVICs. MVICs from MI sheep were less responsive to BMP4 pro-osteogenic stimulation (as reflected by blunted increased in ID2, osteopontin and osteocalcin mRNA) than control. MVICs from sheep with MR had a diminished COL1A1 mRNA response to TGFβ1 and enhanced pro-chondrogenic RUNX2 and SOX9 mRNA response to BMP4 vs. non-MR MVICs. Baseline CD45 expression was detectable only in MR MVICs. Upon TGFβ1 stimulation, CD45 expression was detected in all groups. Immunostaining confirmed increased presence of CD45+ cells in IMR MV interstitium.

Conclusions:
MVs from sheep developing MR had altered TGFβ/BMP response, which may be partially mediated by increased CD45+ fibrocyte presence. Pharmacological strategies aimed to modulate TGFβ/BMP signaling after MI may protect from pathological MV remodeling leading to IMR.
Abstract 15015: Eicosapentaenoic Acid, but Not Docosahexaenoic Acid or a Mixed Omega-3 Fatty Acid Supplement, Inhibits Low-density Lipoprotein Oxidation in a Time-dependent Manner
Authors: Sherratt Samuel , Libby Peter , Bhatt Deepak L , Mason Preston
Published: November 2020

Background:
Eicosapentaenoic acid (EPA), an omega-3 fatty acid (O3FA), reduces oxidation of low-density lipoproteins (LDL) in patients with hypertriglyceridemia, an effect that may contribute to lower cardiovascular (CV) events as reported in the REDUCE-IT trial. By contrast, DHA-containing products have failed to show a reduction in CV events, which may be due, in part, to differences in antioxidant activity. We compared the effects of EPA versus DHA and a mixed O3FA (EPA/DHA) supplement on oxidation of human LDL
in vitro
.

Methods:
LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL, and incubated at 37°C for 30 min in the absence (vehicle) or presence of EPA, DHA, or mixed O3FA supplement at equimolar levels (2.5 μM). All samples were then subjected to copper-induced oxidation (20 μM) as measured by formation of malondialdehyde (MDA). The FA content of the O3FA supplement was measured using gas chromatography/mass spectrometry.

Results:
EPA significantly inhibited LDL oxidation in a time-dependent manner compared with vehicle; after 4 hours, EPA inhibited MDA levels by 96% compared with the vehicle oxidation level (0.51 ± 0.01 vs 11.4 ± 0.4 μM;
p
<0.001). While DHA exhibited antioxidant activity at 2 hours at a level below EPA (2.5 ± 0.1 vs 11.4 ± 0.4;
p
<0.001), even this level of activity was lost by 4 hours. The mixed O3FA supplement failed to show any antioxidant activity through 4 hours (11.4 ± 0.5 μM). Fatty acid analysis showed that the O3FA supplement, in addition to EPA and DHA, contained more than 30 other fatty acids, including saturated fats, that may have nullified any potential benefits.

Conclusions:
These data support potent LDL antioxidant effects of EPA that were sustained over time compared with DHA, which had a weaker, transient effect, or a mixed O3FA supplement, which had no beneficial effect at all. This potent antioxidant mechanism of EPA may contribute to reduced CV risks seen in REDUCE-IT compared with negative findings from trials using DHA-containing formulations.
Abstract 15023: Junctophilin-2 (JPH2) Interactome in Ventricular Myocytes is Subcellular Compartment-dependent and Subject to Remodeling During Hypertrophy Leading to Heart Failure
Authors: Bernas Tytus , Veeraraghavan Rengasayee , Zachary Wilson T , Andrew Soltisz , Jiang Min , Tseng Gea-ny
Published: November 2020

Introduction:
Junctions between sarco/endoplasmic reticulum (SR/ER) and sarcolemma (SL), where Ca-induced Ca release (CICR) takes place, are important for myocardial contractility. JPH2 is the major SR/SL tether in cardiomyocytes.

Hypothesis:
JPH2 interacts with diverse proteins depending on its subcellular location. Furthermore, JPH2's distribution and relations with its interactors are subject to remodeling in diseased state.

Methods:
We studied spontaneously hypertensive rats: 2-3 months (SY, healthy) and ≥ 20 months (SO, in heart failure). We used immunoprecipitation (IP) and global unbiased search (proteomics) to identify JPH2's interactors in cardiomyocytes. We used high-resolution structured illumination microscopy (SIM) followed by deconvolution and object-based segmentation in 3 dimension (OBS3D) to quantify spatial relationships between JPH2 and interactors.

Results:
Based on proteomics JPH2's interactors are involved in: SR/ER function, vesicular transport, sub-sarcolemma scaffold, ion transporters/channels, intercalated disc (ICD) organization and mitochondrial function. We quantified spatial relationships between JPH2 and 6 interactors representing distinct subcellular compartments: RyR2 (junctional SR), Cav1.2 (t-tubules), dystrophin (peripheral SL), caveolin-3 (caveolae), connexin-43 (ICD), and prohibitin-1 (mitochondria). In SY myocytes, JPH2 clusters are organized along the z-lines and peripheral SL, consistent with close and reciprocal association in JPH2/RyR2 and JPH2/dystrophin. In SO myocytes, JPH2 is dispersed from z-lines but stays close to peripheral SL and clusters to ICD. This leads to reduced proximity between JPH2 and Cav1.2 or RyR2, but closer proximity to connexin-43.

Conclusions:
In failing heart, a portion of JPH2 shifts from t-tubule/SR junctions (where CICR occurs) to ICDs (where store-operated Ca entry 'SOCE' occurs), likely contributing to dysregulation of intracellular Ca handling.
Abstract 15046: Arrhythmia Profile in Female Atrial Fibrillation Patients With versus Without Autoimmune Disorders
Authors: Mohanty Sanghamitra , TRIVEDI CHINTAN G , Gallinghouse Joseph , Della Rocca Domenico G , Gianni Carola , MacDonald Bryan , Mayedo Angel , Baqai Faiz M , Bassiouny Mohamed , Gallinghouse G , Burkhardt John , Horton Rodney , Al-ahmad Amin , Di Biase Luigi , Natale Andrea
Published: November 2020

Background:
Autoimmune disorders (AuID) are pro-inflammatory conditions and inflammation is known to promote atrial fibrillation (AF). We evaluated the arrhythmia profile in female AF patients with vs without AuID.

Methods:
Consecutive female patients undergoing their
first
catheter ablation at our center were included in the analysis and divided into two groups;
group 1:
with AuID (n=192) and
group 2:
no AuID (n=2324). All received PV isolation + isolation of left atrial posterior wall and superior vena cava. Additionally, non-PV triggers identified by isoproterenol-challenge were ablated in all.Patients were included in group 1 if they had an established diagnosis of Type 1 Diabetes (DM), rheumatoid arthritis (RA), Lupus, inflammatory bowel disease (IBD), Psoriasis, Sjogren syndrome, Grave’s disease or Celiac disease.

Results:
Baseline characteristics of the study groups are provided in table 1. Most prevalent AuID were DM (56, 29%), RA (52, 27%), Lupus (35, 18.2%) and IBD (40, 20.8%). Patients with AuID were significantly younger and more had non-paroxysmal AF. They also had larger LA diameter and lower LVEF compared to the group with no AuID. Significantly higher number of non-PV triggers were detected in group 1 patients (149 (77.6%) vs 883 (38%), p<0.001). After 2.5 years of follow-up, 139 (72.4%) and 1775 (76.3%) patients from group 1 and 2 were arrhythmia-free off-AAD (p=0.1).

Conclusion:
Women with autoimmune diseases experienced AF at an earlier age with significantly more non-paroxysmal AF compared to those without. However, similar ablation success was observed in both groups that could be attributed to the ablation strategy including all detectable non-PV triggers.
Table:
Abstract 15047: Effects of Blood Pressure Percentile, Body Mass Index, and Race on Left Ventricular Mass in Children
Authors: Udine Michelle L , Kaltman Jonathan , Li Qianxi , Liu Jin , Sun Deyu , Cheung Man Ching , Sabouni Sam , Al Dulaimi Ahmed , SABLE Craig A
Published: November 2020

Introduction:
Childhood hypertension, obesity, and left ventricular hypertrophy (LVH) are risk factors for premature cardiovascular events in adulthood, particularly among minorities. In children, race and body mass index (BMI) have been shown to be independently associated with LVH, with conflicting data on the association of systolic blood pressure (SBP) level with risk of LVH and utility of ECG in assessing LVH. This study looks at the association of SBP percentile, race, and BMI with LVH on electrocardiogram (ECG) and echocardiogram (echo) to define populations at risk.

Methods:
This is a retrospective cross-sectional study design utilizing a data analytics tool (Tableau) combining ECG and echo databases from 2003-2020. Customized queries identified patients ages 2-18 years old who had an outpatient ECG and echo on the same date with available SBP and body measurements. Cases with congenital heart disease, cardiomyopathy, or arrhythmia diagnoses were excluded. Echos with left ventricle mass (indexed to height
2.7
) were included. The main outcome was LVH on echo defined as LV mass index greater than the 95
th
percentile for age.

Results:
In a cohort of 13,926 patients, 6.9% of studies had LVH on echo. SBP percentile > 90% has a sensitivity of 36% and specificity of 82% for LVH on echo. LVH on ECG was a poor predictor of LVH on echo (9% sensitivity and 92% specificity). African American race (OR 1.31, 95% CI = 1.11, 1.55, p=.001), SBP percentile > 95% (OR=1.64, 95% CI = 1.37, 1.95, p <.001), and higher body mass index (OR= 7.43, 95% CI = 6.44, 8.55, p <.001) were independently associated with LVH on echo. Figure 1 shows the prevalence of LVH by African American race, obesity, and SBP.

Conclusions:
African American race, obesity, and hypertension are independent risk factors for LVH in children. Outpatient ECG has low utility in screening for LVH.
Abstract 15049: Prognostic Implications of Outpatient N-terminal Pro-b-type Natriuretic Peptide Changes in Patients With Left Ventricular Assist Devices
Authors: Ali Abbas , shetty suchith , Kshetri Rupesh , BRIASOULIS Alexandros , Ruiz dubuque Ernesto , Akintoye Emmanuel , Sharma Umesh C , Alvarez Paulino
Published: November 2020

Objective:
Evaluate the prognostic implications of N-terminal Pro-B-type Natriuretic Peptide measurements in ambulatory patients with continuous flow left ventricle assist devices (CFLVAD).

Methods:
We performed a retrospective study of consecutive patients that had an LVAD implantation at our institution and were discharged from their index hospitalization.

Results:
Between January 31
st
, 2006 and August 21
st
, 2019, 139 patients received a continuous flow left ventricle assist device implant at our institution and survived beyond their index hospitalization. 127 patients (56.2±12.5 years, 78.7 % male) had NT pro BNP measured at 1- and 3-months post discharge in ambulatory settings. The median (IQR) NT-pro BNP levels were 1661 pg/mL (921-2558 pg/mL) at 1 month and 1094 pg/mL (673-2089 pg/mL) at 3 months post discharge. After a median follow up of 17 months, a total of 53 (41.7%) incidents event occurred. Of these, 37 (69.8%) were heart failure hospitalizations and 16 (30.2%) were deaths. For each 1000-unit increase in NT-pro BNP level at 3 months, there was a 17% increase in the risk of heart failure hospitalization or death (HR=1.17, 95% CI=1.04-1.32, p=0.007)). Also, for each 1000-unit decline in NT-pro BNP level between the 1
st
and 3
rd
months, there was an 11% decrease in the risk of heart failure hospitalization or death (HR=0.89, 95% CI=0.77-0.98, p=0.04).

Conclusion:
In ambulatory patients with CFLVAD, increase in NT pro BNP value from one to three months is associated with a significantly increased risk of heart failure hospitalization and death.
Abstract 15053: Vascular Inflammation in Pulmonary Hypertension is Exacerbated by Litaf-dependent Pericyte Signaling
Authors: Condon David , Shamskhou Kian , Nathan Abinaya , Sweatt Andrew , Chakraborty Ananya , Agarwal Stuti , Zamanian Roham , Yuan Ke , De Jesus Perez Vinicio A
Published: November 2020

Introduction:
Pulmonary arterial hypertension (PAH) is a progressive disease which leads to right heart failure and death. Inflammation plays a key role in PAH pathogenesis as evidenced by inflammatory cell infiltrates around pulmonary vascular lesions and elevated patient serum pro-inflammatory cytokine levels. Pericytes are cells that provide mural support, maintain endothelial homeostasis and have immunomodulatory properties as evidenced by their production of cytokines and regulation of endothelial response to injury. Our group has shown that pericytes contribute to vascular remodeling and vessel loss in PAH, but their contribution to perivascular inflammation is unknown.

Hypothesis:
Lipopolysaccharide induced tumor necrosis factor activating factor (LITAF) positively regulates pericyte production of proinflammatory cytokines in PAH which influence activation of endothelial cells to engage in leukocyte recruitment.

Methods:
Healthy donor (HD) and PAH lung pericyte RNA-seq and microarray datasets were analyzed to identify candidate inflammatory pathways. Proteomic analysis was performed using Luminex assay followed by supervised machine learning. Quantitative PCR (qPCR) and western blot (WB) studies were conducted on HD and PAH pericytes exposed to serum starvation, hypoxia, LPS, and CoCl
2
(a HIF activator).

Results:
Network analysis based on RNA-seq, microarray, and Luminex assay data identified LITAF as a potential regulator of inflammatory gene expression. Compared to HD, abundant LITAF expression was visualized in human PAH perivascular lesions. WB of PAH pericytes showed a significant increase in nuclear LITAF compared to HD across all conditions. Pulmonary microvascular endothelial cells (PMVECs) incubated with media from PAH pericytes showed reduced cell-cell junctions and upregulated ICAM and VCAM compared to HD. Incubation of healthy PMVECs with supernatant from LITAF siRNA transfected HD and PAH pericytes showed a decrease in PMVEC proinflammatory cell markers.

Conclusions:
Our data suggest that LITAF-driven pericyte signaling could play a role in promoting vascular inflammation in PAH. We believe LITAF could serve as a potential new therapeutic target in PAH.