bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 12854: Long Term Outcomes of Pulmonary Vein Isolation With Additional Linear Ablation: Insights From the UC San Diego Atrial Fibrillation Registry
Authors: Wang Edward , Kumar Anjali , Aldaas Omar M , Munir Muhammad , Ho Gordon , Hoffmayer Kurt S , Han Frederick , Krummen David , raissi farshad , Feld Gregory K , Hsu Jonathan C , Darden Douglas J
Published: April 2022

Introduction:
Pulmonary vein isolation (PVI) alone or in combination with empiric linear ablations (PVI + lines) at the left atrial roof or mitral isthmus (MI) is often performed in patients undergoing first-time atrial fibrillation (AF) ablation despite lack of evidence of benefit from clinical trials and pro-arrhythmic potential, however real-world long-term follow-up is limited.

Hypothesis:
Patients undergoing PVI + lines will be more likely to experience long-term adverse outcomes as compared to PVI alone.

Methods:
Patients undergoing AF ablation with either PVI or PVI + lines were included with follow-up data from a single institution between 2005 and 2009. Long-term outcomes included late recurrence of atrial tachyarrhythmias (LRAT), defined as AF, atrial flutter, or atrial tachycardia lasting > 30 seconds after the 3-month blanking period, repeat ablation, and cardioversion. Multivariable adjusted Cox regression was used to evaluate long-term outcomes.

Results:
Among 516 patients (64 ± 10 years, 68% male, 31% persistent AF) included, 376 (73%) underwent PVI only and 140 (27%) underwent PVI + lines. Of those with lines, 74 (53%) had both roof and MI line, 61 (43%) had a roof line, and 5 (4%) had a MI line. Predictors of PVI + lines included persistent AF, coronary artery disease, and male sex. Over a median follow-up of 1016 (IQR: 385 - 1752) days, approximately 63% of those with PVI only and 53% of those with PVI + lines experienced LRAT. After multivariable adjustment, there was a trend toward higher risk of LRAT in those with PVI + lines as compared to PVI only (HR 1.35, 95% CI 0.99 - 1.85, p = 0.06). There was no difference in the risk of repeat ablation (HR 0.96, 95% CI 0.63 - 1.45), while those with PVI + lines had a significantly higher risk of cardioversion as compared to PVI only (HR 2.50, CI 1.67-3.73, p<0.001).

Conclusions:
Those receiving linear ablations to complement PVI experienced a trend in higher risk of LRAT as compared with PVI only. While there was no significant difference in the risk of repeat ablations, there was a two-fold higher risk of cardioversion associated with PVI + lines. In line with clinical trial data, these findings suggest that empiric linear ablations are not beneficial, but may also be associated with adverse outcomes in long-term follow-up.
Abstract 12882: Risk Prediction in Adolescent Males With Congenital Long QT Syndrome
Authors: Goldenberg Ilan , Younis Arwa , Chen Anita , Huang David T , Yoruk Ayhan , Aktas Mehmet , ROSERO Spencer Z , Kutyifa Valentina , McNitt Scott , Sotoodehnia Nona , Kudenchuk Peter , Rea Thomas , Arking Dan E , Zareba Wojciech
Published: April 2022

Introduction:
Men and women with either type 1 (LQT1) or type 2 (LQT2) congenital long QT syndrome (LQTS) exhibit differential risk of cardiac events (CEs) after the onset of adolescence.

Hypothesis:
We have recently reported a novel prediction model for LQTS women after the onset of adolescence. We now report a risk prediction model for adolescents LQT1 or LQT2 males that integrates genotype-phenotype data.

Methods:
The prognostic model was derived from the Rochester LQTS Registry through March 2021, comprising 611 males with LQT1 (N=304) and LQT2 (N=307) from age 10 through 20 years. Anderson-Gill modeling was employed to develop risk groups for the endpoint of non-terminal CEs (total number of syncope, aborted cardiac arrest [ACA], and appropriate ICD shocks). The covariates in the CE model were then applied to the endpoint of a first life-threatening event (LTE: ACA, LQTS-related SCD, or appropriate ICD shocks). The prediction model included the following prespecified variables: genotype/mutation-locations, QTc-specific thresholds, history of syncope prior to 10 years of age, and time-dependent beta-blocker therapy.

Results:
During a total follow-up duration of 6048 patient-years, there were a total of 270 non-terminal CEs. The risk-prediction model identified three risk-groups based on genotype-phenotype variables (Figure). Compared with the Low-Risk group, High-Risk patients experienced a pronounced 5.2-fold (p<0.001) increased risk of CEs; Intermediate-Risk patients had a 2.1-fold (p=0.004) risk-increase. The 10-year rates of a first LTE for the Low- Intermediate- and High-Risk groups were 2%, 6%, and 8%, respectively. C-statistic for the CE prediction model was 0.61 (0.56-0.67).

Conclusions:
This is the first risk-prediction model that provides risk-estimates for CE and LTE in adolescent males with either LQT1 or LQT2 based on personalized genotype-phenotype data. The projected risk estimates can be used to guide sex-specific management in LQTS.
Abstract 12905: Left Atrial Appendage Arrhythmias in Patients With Epicardial or Endocardial Occlusive Devices
Authors: Romanowicz Katherine C , COSTEA ALEXANDRU I
Published: April 2022

Background:
The role of left atrial appendage (LAA) isolation in atrial fibrillation (AF) has been extensively studied. As this leads to loss of contractility, the risk for thromboembolism increases. Percutaneous occlusion of the left atrial appendage has been proven to prevent thromboembolisms, however, unlike epicardial ligation of the LAA, it does not provide electrical isolation. As such, the risk of recurrent atrial arrhythmias remains while an arrhythmia source originating around the occlusion device can be problematic.

Objective:
We present three patients with arrhythmias originating from the LAA after endocardial or epicardial occlusion. Utilizing ultra-high-density mapping a definition of arrhythmia circuit was delineated.

Case Studies:
Two patients with prior failed AF ablation prior to WATCHMAN
TM
implantation were referred for a second ablation. We created ultra-high-density maps processed the images with CARTO®3 Coherent mapping. CARTOSOUND® was used to delineate the WATCHMAN
TM
edges. Both patients were found to have arrhythmias originating from the LAA, proximal to the Watchman device. Delivery of radiofrequency ablation on the anterior aspect of the LAA stump in one patient and isolation of the LAA in the other patient terminated the arrhythmias. A third patient had a surgical closure of the LAA using an Atricure ® clamp as part of a conversion procedure. A recurrent arrhythmia was mapped inside the LAA, distal to the occluder. Ablation inside the LAA and through the Atricure® gap terminated the arrhythmia.

Discussion:
It is expected that the increasing prevalence of LAA occlusive devices will lead to an increase in atrial arrhythmias arising from the LAA post-occlusion. Conversely, electrical isolation of the LAA increases stroke risk. As the best staged approach for these patients remains unclear, a concomitant electrical isolation with ablation and LAA occlusion may be the optimal solution. Insufficient data and limiting healthcare economics prevent this approach from becoming a gold standard.

Conclusion:
Our cases confirm the LAA role in recurrent arrhythmias, highlight the difficult ablative management post LAA occlusion and support the use of high density mapping for a successful outcome.
Abstract 12913: Under Pressure: An Unusual Case of Pulmonary Hypertension and Pericardial Effusion
Authors: McLaughlin Megan , Ganz Peter , Durstenfeld Matthew , Hsue Priscilla
Published: April 2022

A 50-year-old male smoker with hypertension presented with subacute bilateral leg swelling, weight gain, and dyspnea. Exam revealed tachycardia, jugular venous distention, peripheral edema, diminished breath sounds, and pulsus paradoxus. Labs were notable for elevated creatinine and leukocytosis. ECG showed sinus tachycardia and low voltages. CXR showed left hemithorax opacification. TTE revealed normal LV function, septal flattening, severely dilated RV with reduced function, RVSP 81 mmHg, and a large pericardial effusion with exaggerated respirophasic variation in mitral inflow but no chamber collapse. The elevated RVSP with RV failure raised concern for acute pulmonary embolism (PE). CT chest excluded PE but revealed a large mediastinal mass compressing both pulmonary arteries (PA) and large left pleural effusion. Pulmonary angiogram demonstrated a totally occluded left PA and severe stenosis of the right PA. Right heart catheterization showed RAP 24, RV 83/21, PA 84/29 (mean 53), intrapericardial pressure 15 mmHg, and low cardiac index (1.6 L/min/m2).

Pericardiocentesis was performed with close monitoring by PA catheter. Removal of 500cc fluid was well tolerated with stable hemodynamics, cardiac output, and intracardiac pressures. Pericardial fluid cytology and lymph node biopsy demonstrated small cell lung cancer. Cautious diuresis was initiated. After one cycle of chemotherapy, repeat CT chest showed reduced extrinsic compression of the right PA with improved lung perfusion. Repeat TTE showed dramatic improvement with normal RV size and function, RVSP 22 mmHg, and trivial pericardial effusion.

Pericardial effusion in the setting of severe PH is associated with poor outcomes and presents both diagnostic and therapeutic challenges. Classic findings of tamponade (e.g. right sided chamber collapse) may be masked by elevated right heart pressures. Compression of the PA by a mediastinal mass is an unusual cause of PH and right heart failure that can mimic acute PE. This rare clinical scenario presents the following challenges: (1) diuresis may precipitate tamponade, (2) pericardiocentesis may enable an already enlarged RV to acutely dilate and thus worsen RV failure, and (3) there is uncertainty regarding the role for PA stenting.
Abstract 12915: Machine Learning Models Show That Age, Functional Status, and TNF-α Accurately Predicts Multimorbidity in Acute Coronary Syndrome
Authors: Breen Katherine , Coultas Jesse , Devon Holli A
Published: April 2022

Introduction:
Increasing prevalence of multimorbidity (>2 conditions) put individuals, especially older adults, at increased risk for acute coronary syndrome (ACS). Machine learning techniques provide an opportunity to identify clinical factors associated with multimorbidity that may aid in identifying subgroups of multimorbid patients that are at higher risk for ACS. Our primary objective was to use machine learning techniques to identify factors associated multimorbidity in individuals presenting to the emergency department (ED) for potential ACS.

Hypothesis:
Markers of chronologic and physiologic aging are associated with multimorbidity and vary by functional status and inflammatory profiles.

Methods:
This was a secondary analysis of data collected from a large multi-site study aimed at characterizing sex differences in symptoms suggestive of ACS in the ED. Variables of interests were measured with the Charlson Comorbidity Index, the Duke Activity Status Index, and serum cytokines (TNF-α, IL-6, and IL-18). A logistic regression model was applied to a sample of 414 patients utilizing a 70/30 test/train split to determine if biomarkers, functional status, sex, and age were associated with multimorbidity.

Results:
Patients were predominantly male (62.5%), white (73.0%), and had a mean age of 58.9 years. The accuracy of the model in predicting multimorbidity was 86.8% in the training set (n=290). In validation testing, accuracy was 73.0% (n=124). Functional status (OR .960, 95% CI .94-.206, p<0.000), age (OR 1.10, 95% CI 1.04-1.10, p<0.000), and TNF- α (OR 2.21, 95% CI 1.17-4.45, p<0.000), were associated with multimorbidity. The overall model was significant with a χ
2
(286, N=71.1) = 6, p>0.05. A responder operator curve was run on the individual variables and age, functional status, and TNF- α and showed significant discrimination levels (c-statistic 0.74, 0.73, and 0.65, respectively).

Conclusions:
Multimorbidity increases the risk for ACS. TNF-α, functional status, and age improved models of ACS risk stratification in a heterogeneous sample of multimorbid patients. Machine learning methodologies exhibit utility in identifying potential clinical markers of multimorbidity.
Abstract 12934: The Association of Health Literacy With Health Status Outcomes in Heart Failure Patients
Authors: Garcia R. Angel , Rothenberger Scott D , Belnap Bea H , Jones Philip , Rollman Bruce L , Spertus John
Published: April 2022

Background:
Low health literacy (HL) is a known barrier to care and is associated with worse overall health status. The association of HL with disease-specific health status in heart failure (HF) patients is unknown. To address this gap we used data from
Hopeful Heart
, a randomized trial examining the impact of two 12-month treatment strategies in patients with HF and depression vs usual care.

Methods:
Health literacy was assessed at baseline via a brief screening tool previously validated in patients with HFrEF, classifying patients into adequate vs. low literacy. HF-specific health status was quantified with the 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) at baseline, 3, 6, and 12 months. Using linear regression, we estimated the association of low HL with 12-month KCCQ-12 Summary Score, adjusting for treatment group, age, gender and LVEF. We also assessed the association of low HL with 12-month change in KCCQ-12, additionally adjusting for baseline score. Finally, we analyzed depression severity as a moderator in the interaction between HL and PROMIS-D depression score.

Results:
Among 756 patients, those with low HL (N=235, 31%) were similar in demographics (65±13 vs 64±13 years; 43% vs. 44% female; 24% vs. 28% non-White), but had less education (36% vs. 61% high school) and employment (10% vs. 19%) compared to those with adequate HL. Mean KCCQ-12 scores were consistently lower in participants with low HL at all time points (Figure). After adjusting for treatment group, age, sex, and LVEF, low HL was strongly associated with lower 12-month KCCQ-12 score (-9.5 points, CI [-13.7,-5.3]). After adjustment for baseline score, low HL remained associated with less improvement in KCCQ-12 (-5.9 points, CI [-9.7, -2.2]). Depressive symptoms did not moderate this association (interaction p=0.72).

Conclusion:
In patients with HF, low HL is associated with worse disease-specific health status and with poorer recovery in health status at 12-month follow up.
Abstract 12959: Clonal Hematopoiesis of Indeterminate Potential Predicts Incident Venous Thromboembolism in the UK Biobank Cohort
Authors: Dikilitas Ozan , Saadatagah Seyedmohammad , Satterfield Benjamin , Kullo Iftikhar J
Published: April 2022

Introduction:
Clonal hematopoiesis of indeterminate potential (CHIP) refers to the formation of genetically distinct subpopulations of blood cells due to somatic mutations. CHIP is associated with a variety of adverse outcomes, including hematological cancers, cardiovascular disease, and death. We sought to investigate the association of CHIP with incident venous thromboembolism (VTE).

Methods:
We analyzed exome sequence data from 200,628 individuals in the UK Biobank cohort using Mutect2 to identify a prespecified list of somatic mutations in
DNMT3A, TET2,
and
ASXL1,
which are known genetic drivers of CHIP. CHIP was defined as harboring a somatic mutation at a variant allele fraction (VAF) ≥10% and individuals with VAF <2% were deemed as non-carriers. VTE was ascertained using verbal interview data and diagnostic/procedural codes and defined as a composite of the following: thrombophlebitis of deep veins of lower limbs, embolism/thrombosis of vena cava, pulmonary embolism, venous thrombectomy of lower limb veins or IVC filter insertion. We implemented a nested case-control design with incidence density sampling to identify incident cases and controls matched (1:8 ratio) for sex, smoking status, and history of malignancy at baseline. Conditional logistic regression analysis adjusted for age, BMI, and genetic ancestry was performed to assess the association between CHIP and incident VTE.

Results:
Among 200,628 individuals, we identified 3,885 individuals with CHIP at baseline and 748 incident VTE events during a median follow-up of 9.2 years. In 748 incident cases and 5984 matched controls, CHIP was associated with increased risk of incident VTE independent of conventional risk factors for VTE, namely, age, sex, BMI, smoking, and history of malignancy (incidence rate ratio [95% confidence interval]; 1.60 [1.04-2.46], p=0.032). When we restricted the cases to individuals with incident pulmonary embolism (n=441), we observed a stronger association with CHIP (1.80 [1.08-3.05], p=0.025).

Conclusions:
CHIP is associated with increased risk of VTE independent of history of malignancy and other conventional risk factors. The pathophysiological basis for this association needs further investigation.
Abstract 12960: Identifying Gaps in Practice Patterns for Routine Lipid Profiles and High-Intensity Statins in Acute Myocardial Infarction Patients Prior to an Acute Coronary Syndrome Event
Authors: Nieves La Cruz Carlos , Holden Patricia R , Abreu Vera Nitza , Scott Jamessa , Friant Janet , Hickey Stacia B , Pargulski Anastasia
Published: April 2022

Introduction:
According to the 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction, admitting orders for the patient with STEMI should include a serum lipid profile in laboratory tests. Subsequently, the 2018 Guideline on the Management of Blood Cholesterol guidelines state that in primary prevention statins are recommended for patients with severe hypercholesterolemia and in adults 40 to 75 years of age either with diabetes mellitus or at higher ASCVD risk.

Methods:
A baseline review of data from Get With The Guidelines® - CAD across 10 pilot sites was conducted. An initial 430 patients were excluded from the Ezetimibe Considered for Very High-Risk Patients measure due to missing data fields. Interviews were conducted with participating sites to determine the root cause of the incomplete data.

Results:
The root cause analyses resulting from these interviews and case studies revealed that lipid profiles were not consistently performed. Further, only two patients were included in the numerator for the Ezetimibe Considered for Very High-Risk Patients measure. An analysis of 455 eligible patients showed that 70% of AMI patients seen by these hospitals were not presenting on any statin therapy prior to their acute event.

Conclusions:
Despite the clinical guideline recommendations for lipid management for both acute and secondary prevention, there remains much room for improvement. Preliminary results from this learning collaborative highlight the need for improved lipid profiling practices in the acute setting for STEMI patients and an opportunity for intervention through modifiable risk factor reduction in the form of statin therapy in the outpatient setting. We have identified a gap in AMI patient care, which presents the opportunity to improve long-term patient outcomes through heightened lipid profile collection sensitivity. At a systemic level, further research needs to be conducted to determine why patients are presenting with severe acute coronary events without prior management of their blood cholesterol levels. We hope through continued studies with the pilot sites we will observe a shift in practice patterns and improved non-statin lipid-lowering medication consideration for very high-risk ASCVD patients.
Abstract 12996: Prospective Study of Patient Reported Outcomes and Costs Associated With Same Day Discharge and Vascular Closure for Atrial Fibrillation Ablation
Authors: Steinberg Benjamin A , Woolley Shannon , LI HAOJIA , Maires Chase , Groh Christopher , Navaravong Leenhapong , Ranjan Ravi , Zhang Yue , Bunch T. J
Published: April 2022

Introduction:
Overnight stay after ablation for atrial fibrillation (AF) is standard practice, in part driven by the need for bedrest required to maintain hemostasis. We aimed to measure patient reported outcomes (PROs) and costs associated with same day discharge (SDD) for AF ablation and vascular closure device implantation in clinical practice.

Methods:
PROs were measured in 50 patients prospectively enrolled prior to AF ablation with post procedure treatment by complete vascular device closure (n=25) versus compression hemostasis (n=25). Health-system costs for SDD patients receiving vascular device closure were compared to matched controls with one-night stays who did not receive closure devices.

Results:
Patients receiving vascular device closure for AF ablation had mean age 65, 17% female, with mean CHA
2
DS
2
-VASc score 3. Mean number of venous sheaths was higher among patients receiving vascular device closure (3.8 vs. 3.1, p<0.001), and there was 1 case of re-bleeding in a patient receiving vascular closure device (no other vascular complications). Same-day discharge rates (76% vs. 8.3%, p<0.001), patient satisfaction with bedrest time (8.5 vs. 6, p=0.004) and with pain (8 vs. 5.1, p=0.009) were significantly higher among patients receiving vascular closure. For health-system costs, patients with vascular closure the mean age was 66, 36% were female, with a mean CHA
2
DS
2
-VASc score of 2 (p=NS for each vs. matched controls). SDD with vascular closure was associated with significantly lower facility, pharmacy, and disposable costs, but higher implant costs (
Table
). Overall costs for ablation were not different based on conservative estimates for overnight stay costs.

Conclusions:
Vascular closure for AF ablation improves patient experience in routine clinical care. Use of vascular closure and SDD after AF ablation reduces several components of health system costs, without an overall increase, and may be cost-saving in comparative healthcare systems.
Abstract 12998: S-Cysteinylation of Plasma and Serum Albumin is Associated With Risk Factors of Atherosclerotic Cardiovascular Disease
Authors: Wilson Zachary , Olagunju Abdulbaril , Elias Ghazwan , Krause Daniel , Pham Linda , Kang Paul , Jeffs Joshua , Jehanathan Nilojan , Kapuruge Erandi , Borges Chad , Breburda Christian S
Published: April 2022

Introduction:
Albumin oxidation or S-cysteinylation (S-Cys) of its free cysteine residue has been shown to be a measure of oxidative stress. While it is subject to artificial ex-vivo elevations, freshly processed samples could serve as a theoretical biomarker of any number of inflammatory states.

Hypothesis:
S-Cys Albumin is associated with atherosclerotic cardiovascular disease (ASCVD) and its risk factors that increase oxidative stress.

Methods:
We enrolled 137 patients evaluated for chest pain in a single-center cross-sectional study from May 2016 through March 2020. Plasma and serum samples were gathered and immediately processed for analysis of intact albumin by high pressure liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). Statistical analysis included a spearman’s coefficient, and two-tailed linear regression of the relative fractional abundance (RFA) of S-Cys albumin and clinical variables.

Results:
S-Cys-albumin levels were significantly decreased in those with a previous history of coronary stenting (Plasma β=-0.032, p=0.005; Serum β=-0.032, p=0.012; n=24) and MDD (Plasma β=-0.016, p=0.132; Serum β=-0.026, p=0.021, n=34). S-Cys-albumin levels were significantly elevated in those with a previous history of peripheral artery disease (Plasma β=0.051, p=0.015; Serum β=0.055, p= 0.016; n=6) and chronic infections (Plasma β=0.023, p=0.033; Serum β=0.021, p =0.069; n=30). CAD by history was not significantly different (Plasma β=0.012, p=0.19; Serum β=0.01, p =0.3; n=57). Spearman’s coefficient demonstrated a positive correlation between age (plasma rho = 0.1877, p = 0.0576; serum rho 0.2641, p = 0.007; n=103), BMI (plasma rho = 0.2089, p = 0.0342; serum rho = 0.1287, p = 0.195; n=103), Framingham risk score (plasma rho = 0.2607, p = 0.0523; serum rho = 0.3595, p = 0.0065; n=56), ASCVD risk score (plasma rho = 0.3526, p = 0.0083; serum rho = 0.472, p = 0.0003; n=55), heart rate (plasma rho = 0.2225, p = 0.0239, serum rho = 0.1678, p = 0.0902; n=103) and NT-pro-BNP (plasma rho = 0.3398, p = 0.0319; serum rho 0.3937, p = 0.012; n=40).

Conclusion:
S-Cysteinylated Albumin is associated with several measure of ASCVD and its risk factors. It may be a marker of the underlying oxidative stress.
Abstract 13223: Split-Intein Mediated Adeno Associated Virus Delivery of CRISPR/dHFCas9-TET3CD as Antifibrotic Therapy
Authors: Xu Xingbo , Hulshoff Melanie S , Tan Xiaoying , Maamari Sabine , Krenning Guido , Hasenfuss Gerd , Zeisberg Michael , Müller Oliver J , Zeisberg Elisabeth
Published: April 2022

Introduction:
Cardiac fibrosis is characterized by excessive deposition of extracellular matrix for which no specific therapy is available as of yet. Gene methylation plays an important role in the progression of cardiac fibrosis. We previously demonstrated that high-fidelity CRISPR/Cas9-based gene-specific hydroxymethylation rescues gene expression of fibrosis suppressor genes and attenuates renal fibrosis. Its efficacy in treating cardiac fibrosis, however, has not been examined.

Hypothesis:
While AAV-mediated delivery of CRISPR/Cas9 holds great therapeutic potential to treat cardiac fibrosis, several challenges still need to be overcome. We here aimed to circumvent the limiting viral packaging capacity of AAVs, and to identify the best AAV serotype to target mouse cardiac fibroblasts.

Methods:
We utilized split-intein mediated protein-splicing to divide dHFCas9-TET3CD (dHFCas9 fused to the catalytic domain of TET3) into two parts in order to perform AAV-mediated gene-specific demethylation of a fibrosis suppressor gene. Moreover, we explored the efficacy of 9 different serotypes in targeting mouse cardiac fibroblasts. To explore the antifibrotic efficacy of the fused dHFCas9-TET3CD in vivo, the Angiotensin-II induced cardiac fibrosis mouse model was used.

Results:
We identified that AAV9-SLRSPPS has a tropism for mouse cardiac fibroblasts with an efficiency of 72% in vitro and 51% and 32% in vivo after 7 days and 4 weeks, respectively. We showed that upon AAV transduction, the fused dHFCas9-TET3CD protein leads to gene-specific demethylation and attenuates cardiac fibrosis in the Angiotensin-II induced cardiac fibrosis mouse model .

Conclusions:
We demonstrate the use of a Cas9 derivative (dHFCas9-TET3CD) in combination with the split-intein technology and the AAV9-SLRPPS serotype to perform targeted demethylation both in vitro and in vivo which results in amelioration of cardiac fibrosis in vivo. This new technology holds promise not only for cardiac disease but for any disease associated with hypermethylation as well as for other applications where CRISPR/Cas9 in combination with AAV is useful.
Abstract 13245: Cardiovascular Risk Burden in Relation to Dementia and Brain Structural Imaging Markers: A Study From UK Biobank
Authors: Cao Yaying , Feng Chengwu , Chen Jing , Gan Wei , Ma Yuan , Hu Yonghua , Dhana Klodian , Shen Jie , zheng yan , Yuan Changzheng , Zong Geng
Published: April 2022

Introduction:
Cardiovascular risk burden is associated with higher all-cause dementia risk. However, the roles of cardiovascular disease (CVD) and genetic background, and the associations of cardiovascular risk burden with dementia subtypes and brain structure, need to be examined.

Hypothesis:
We hypothesized that the Framingham General Cardiovascular Risk Score (FGCRS) would be associated with all-cause and subtypes of dementia and brain structure.

Methods:
We conducted a prospective study among 354,654 participants free of CVD and dementia at baseline (2006-2010, mean age 56.4 years) within UK Biobank. CVD risk burden was evaluated by baseline FGCRS. Dementia case was identified from hospital inpatient records and death register data. Brain MRI volume markers were available for 15,104 participants since 2014. Logistic and linear regression models were used for dementia risk and brain volumes, respectively.

Results:
During a median 12.0 years of follow-up, 3,996 all-cause dementia cases were identified. Higher FGCRS was associated with an increased all-cause dementia risk after adjusting for demographic, major lifestyle, clinical factors, and polygenic risk score (PRS) of Alzheimer’s disease (AD). Comparing the high vs. low tertile of FGCRS, the odds ratios (ORs) and 95% CIs were 1.26 (1.12, 1.42) for all-cause dementia, 1.67 (1.33, 2.09) for AD, and 1.53 (1.08, 2.17) for vascular dementia (all P
trend
< 0.05). Incident stroke and coronary heart disease accounted for 13% (95% CI: 9%, 19%) of the association of FGCRS with all-cause dementia. Interaction was not detected for FGCRS and PRS on risk of all-cause or any subtype of dementia (all P
for interaction
> 0.05). We observed an 83% (95% CI: 47%, 128%) higher all-cause dementia risk comparing the high-high vs. low-low for FGCRS-PRS category. For standardized brain volumes, higher FGCRS was associated with greater log-transformed white matter hyperintensities, smaller cortical volume, and smaller grey matter volume.

Conclusions:
Cardiovascular risk burden was associated with higher dementia risk and neurodegeneration-related brain volume markers. The association of cardiovascular risk burden with all-cause dementia was partly explained by CVD onset and independent of dementia genetic risk.
Abstract 13251: Left Bundle Branchpacing Post-Atrioventricular Junction Ablation for Atrial Fibrillation: A Propensity Score Matching Analysis
Authors: Huang Weijian , Cai Mengxing , Wu Shengjie , Su Lan , Wang Songjie , Zheng Rujie , Jiang Limeng , He Yanlei , Zhu Ling , Lian Liyou , Ellenbogen Kenneth
Published: April 2022

Introduction:
Although left bundle branch pacing (LBBP) has emerged as a novel pacing modality which can allow for safe atrioventricular junction (AVJ) ablation and lower pacing threshold compared to His bundle pacing (HBP), its long-term safety and efficacy in patients with atrial fibrillation (AF) is still unknown.

Hypothesis:
This study aimed to examine the long-term clinical feasibility, safety, and efficacy of LBBP in AF patients post-AVJ ablation and provide a balanced comparison of LBBP versus HBP.

Methods:
This study prospectively enrolled patients with AF and heart failure (HF) who underwent AVJ ablation and LBBP from July 2017 to December 2019. The control group patients were selected, by propensity score (PS) matching with a 1:1 ratio, among those HBP implantations performed in the years 2012-2019.

Results:
A total of 99 patients were enrolled in this study, with successful permanent LBBP post-AVJ ablation in 100% of patients (primary LBBP: 76; secondary LBBP: 23). Significantly improvements were observed in LVEF, tricuspid regurgitation, and mitral regurgitation at 1-year follow-up (p<0.05). The proportion of patients whose acute threshold <1
V@0.5ms
was 97.9% and only one patient had an increase in threshold ≥1
V@0.5ms
at 1-year follow-up. Further, patients with LBBP as an active-group was compared to patients with HBP (control-group) through PS matching with 170 successfully matched (PS-HBP, N=85; PS-LBBP, N=85). In the control-group, the success rate of permanent HBP was 81.9% (176/215), which was lower than that with LBBP (p<0.001). No significant differences in clinical outcomes were observed between groups (p>0.05), while lower thresholds, greater sensed R-wave amplitudes, and less complication were observed in PS-LBBP group (p<0.05).

Conclusions:
LBBP is feasible, safe, and effective in AF and HF patients post-AVJ ablation, which has comparable clinical benefit, higher success rate, better pacing parameters, and less complication than HBP.
Abstract 13252: Is There a Gender-Specific Association Between High Coronary Artery Calcium Score and High Polygenic CAD Risk Score?
Authors: Saad Shaukat Muhammad Hamza , Rynders Beatrice , Petrasko Mark , Hajek Catherine , Petrasko Phillip , Pham Melissa , stys patryk , Sjovold Alexander , Stys Veronica , Singh Komaldeep , Coy Kevin , Lubke Michael , Sincan Murat , Stys Adam , Petrasko Marian S , Stys Tom
Published: April 2022

Introduction:
Genetic predisposition for CAD is well established. Polygenic risk scores are emerging as tools which attempt to quantify the genomic component of an individual’s risk for CAD. However, their clinical utility for individual risk stratification is unclear.

Hypothesis:
180 SNPs previously identified in Caucasian Genome Wide-Association Studies for CAD were used to construct a weighted restricted polygenic risk score (PRS; normalized range 11.18 -17.58). This study hypothesizes a gender-specific association between high PRS (>=85th percentile) and high coronary artery calcium score (CAC) score, defined as >400.

Methods:
Between January 2018 & March 2020, 21,784 patients underwent CAC screening and/or PRS testing. Caucasian patients with both PRS and CAC scores were identified. Fisher’s exact test was utilized to test the association between high PRS and high CAC in men and women.

Results:
Both PRS and CAC were available for 3,197 Caucasian patients, out of which 2,106 (65.8%) were women (figure 1: gender adjusted PRS distribution). Odds ratio of high PRS and high CAC was 1.64 (95% CI: 0.86-2.97; p >0.05) in women and 1.59 (95% CI: 0.98 - 2.53; p>0.05) in men.

Conclusions:
There is no statistically significant, gender-specific association between high PRS and high CAC in our Caucasian cohort. However, there is a trend suggestive of a positive correlation in women. This clinical data is the first of its kind in a real world setting on the use of PRS for CAD risk assessment. Larger, ethnically diverse studies are needed.
Abstract 13259: IRX5 Transcription Factor Cooperate With TBX5/GATA4/NKX2-5 Complex to Regulate Several Human Cardiomyocyte Functions
Authors: Canac Robin , Cimarosti Bastien , Girardeau Aurore , Forest Virginie , Fourgeux Cynthia , Poschmann Jeremie , Lamirault Guillaume , Lemarchand Patricia , Gaborit Nathalie
Published: April 2022

Introduction:
The transcription factor (TF) Iroquois homeobox 5 (Irx5) is a key patterning and differentiation regulator. In humans, IRX5 regulates the expression of the main cardiac sodium ion channel gene,
SCN5A
. However, its global mechanistic role in human cardiomyocytes is still to be fully understood. Hamamy syndrome patients, carrying
IRX5
mutations, have defects in various organs including the heart and the limbs. Interestingly, heart and limbs defects are also found in Holt-Oram syndrome patients (
TBX5
mutations), suggesting a functional link between TBX5 and IRX5. Moreover, a cooperation of TBX5 with GATA4 and NKX2-5 in cardiac development and functions has already been shown.

Hypothesis:
We hypothesized that IRX5 may cooperate with the TF complex TBX5/GATA4/NKX2-5 to regulate key cardiac functions in humans.

Methods & Results:
First, immunoprecipitations in HEK293 cells showed that IRX5 can bind to TBX5, GATA4 and NKX2-5, individually and together as a complex. Using five truncated forms of IRX5 protein, its homeodomain was identified as being the essential protein region for these interactions. Second, we showed by luciferase assays, that each combination of these TFs impacted differently
SCN5A
expression:
e.g.
by itself, NKX2-5 has a strong activator effect (increased activity by 10 fold
vs
. no TF) that is potentialized by IRX5 (12 fold
vs
. no TF) but inhibited by TBX5 (8 fold
vs
. no TF). Third, genes bound by IRX5 (n=2253) were identified by ChIP-Seq on cardiomyocytes derived from induced pluripotent stem cells generated from 2 healthy individuals. Analyzing published ChIP-Seq datasets for TBX5, GATA4 or NKX2-5 in the same cellular model, we identified 2990 genes that were bound by these 3 TFs, and associated with cardiac biological pathways, such as muscle contraction. Among these genes, 848 were also bound by IRX5 and were associated with the function of electrical activity and with the fibrosis signaling, suggesting a specific role for IRX5 in these cardiac processes.

Conclusions:
Overall, our data show new physical and functional interactions between IRX5 and 3 key cardiac TFs (TBX5, GATA4 and NKX2-5), and suggest an unexpected regulatory role for IRX5 in specific human heart functions.
Abstract 13272: Modeling Cardiotoxicity Utilizing Human Pluripotent Stem Cell-Derived Cardiomyocytes: Towards Protective Therapy for the Heart
Authors: Schwach Verena , Slaats Rolf H , Cofino Fabres Carla , ten Den Simone A , Rivera-Arbelaez Jose , van der Zanden Sabina , Neefjes Jacques , Ribeiro Marcelo C , Cao Lu , Passier Robert
Published: April 2022

Introduction:
Cardiotoxicity is one of the main adverse effects of cancer therapy and has been extensively assessed in animal models which are not predictive for drug-induced cardiotoxicity in humans. Human pluripotent stem cell (hPSC)-derived cardiomyocytes provide a reliable source of human cardiomyocytes and have already proven valuable for cardiotoxicity studies. We present here a versatile screening platform, utilizing hPSC-cardiomyocytes, for assessing different aspects of cardiotoxicity.

Methods and Results:
A well-known group of anticancer drugs that cause therapy induced cardiotoxicity are anthracyclines. To validate their toxicity on human cells we compared the uptake of Doxorubicin (DOXO) and two of its analogues Amrubicin (AMR) and Aclarubicin (ACLA) into cardiomyocytes and fast dividing hPSCs. We utilized high throughput time-lapse imaging of cardiomyocytes differentiated from an NKX2.5
eGFP
-α-actinin
mRuby2
hPSC reporter for assessment of viability and sarcomeric disarray by creating binary masks of the fluorescent area. After 5 days less than 25% of sarcomeres were still present and about 20% of cardiomyocytes survived treatment with 1 μM DOXO or ACLA. Moreover, we evaluated the cardiotoxic effect on a functional level by evaluating calcium transients and identified faster rates after DOXO or ACLA treatment. In addition to analysis in 2D monolayers, we also established a more advanced platform for creating 3D engineered heart tissues, more closely resembling the human heart, which allowed us to measure the effect of a cumulative drug dose on cardiac contraction. We quantified contractile force and kinetics every 12 h for 3 days and observed total loss of contraction 60 h after treatment with 5 or 10 μM DOXO, 75% reduction with 5 μM ACLA and no loss of contraction with 5 μM AMR.To study different damage mechanisms, we investigated apoptotic marker Annexin V, DNA damage marker pH2AX, calcium accumulation and expression of cardiac genes.

Conclusion:
These assays enabled us to study the cardiotoxic effect of DOXO and two analogues on hPSC-derived cardiomyocytes. Most importantly, treatment with AMR had no effect on cardiac function. Ultimately our platform for assessing cardiotoxicity will lead to a better and safer treatment of patients.
Abstract 13279: Real-Time Arrhythmia Detection in Intensive Care Unit Using a Hybrid Convolutional Neural Network Approach
Authors: Bollepalli Sandeep Chandra , Sevakula Rahul K , Au-Yeung Wan-Tai M , Kassab Mohamad , Merchant Faisal M , Bazoukis George , Boyer Richard , Isselbacher Eric M , Armoundas Antonis
Published: April 2022

Background:
Intensive care units (ICUs) admit high-risk patients whose physiological parameters are continuously monitored to provide timely care. However, traditional ICU monitors are known to generate high rate of false alarms (FAs) resulting in alarm fatigue. In this work, we investigate the use of a hybrid convolutional neural network (CNN) architecture aiming to reduce the burden of FAs.

Methods and Results:
We retrospectively analyzed 953 independent life threatening alarms from the streaming data of 410 ICU patients. Specifically, we used four channels of electrocardiographic (ECG), arterial blood pressure (BP) and photoplethysmographic (PPG) signals to detect noise in each of the physiological signals, as well as the onset of an arrhythmia. To this end, we developed a hybrid CNN architecture that fuses the information from multiple physiological signals as well as the handcrafted features (Figure 1). Using 5-fold cross validation repeated for 5 times, we obtained an arrhythmia detection accuracy of 87.5% with a standard deviation of 0.5% (Table 1). In practice, the proposed hybrid-CNN algorithm would have suppressed 77.05% of the FA generated by an existing monitoring system, without prior knowledge of the underlying alarm, which is superior to any other published algorithm. Evaluation on the PhysioNet 2015 Challenge database achieved an overall classification accuracy of 93.9%, indicating its efficacy and generalizability. Further, our method remains adaptable to various arrhythmic conditions as well as multiple physiological signals.

Conclusions:
A hybrid CNN architecture can significantly reduce FA burden and hence improve the quality of care in ICUs
Abstract 13300: Does Mechanical Dyssynchrony in Addition to QRS Area Ensure Sustained Response to Cardiac Resynchronization Therapy?
Authors: Wouters Philippe C , van Everdingen Wouter , Vernooy Kevin , Geelhoed Bastiaan , Allaart Cornelis , Rienstra Michiel , Maass Alexander H , Vos Marc A , PRINZEN Frits W , Meine Mathias , Cramer Maarten J
Published: April 2022

Introduction:
Judicious patient selection for CRT may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRS
AREA
, and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively.

Hypothesis:
We hypothesize that the presence of combined electrical and mechanical dysfunction are of added benefit in predicting a sustained CRT-response.

Methods:
A total of 240 CRT patients were prospectively enrolled from six centers. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6 month, and 12 month follow-up. QRS
AREA
was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥ 15% decrease in LVESVi, at both 6 and 12 month follow-up. Presence of left bundle branch block (LBBB) was determined according to strict American Heart Association criteria.

Results:
QRS
AREA
and SRSsept were both strong, multivariably adjusted, predictors of reverse remodelling. The presence of SRSsept ≥ 2.5%, in addition to QRS
AREA
≥ 120 μVs, significantly increased the extent of reverse remodelling when compared to high QRS
AREA
alone (ΔLVESVi 38±21 versus 22±21%). As a result, 100% of LBBB-patients and 74% of non-LBBB patients with combined electrical and mechanical dysfunction were sustained volumetric responders, as opposed to 53% and 46% with high QRS
AREA
alone, respectively.

Conclusions:
In patients with high QRS
AREA
, concomitant presence of high SRSsept significantly increases 6-month remodelling after CRT. Combined presence of high SRSsept and QRS
AREA
, but not high QRS
AREA
alone, is of importance in order to ensure a sustained response after CRT in LBBB patients.
Abstract 13316: Cardiomyopathy Induced by Metabolic and Hypertensive Stresses is Alleviated by SARM1 Deficiency
Authors: Light Christine , Lee Chi Fung
Published: April 2022

Introduction:
NAD depletion emerges as a hallmark of diseases. Strategies to replenish NAD levels have shown promise to treat heart disease, including heart failure with preserved ejection fraction (HFpEF). However, how NAD consumption mechanisms lead to NAD depletion are less understood. SARM1 is a novel intracellular NAD hydrolase that promotes axonal degeneration after axon injury, and its role in cardiomyopathy has not been tested.

Hypothesis:
We hypothesized that SARM1 deficiency will protect hearts against cardiomyopathy induced by metabolic and hypertensive stresses.

Methods and Results:
Aged-matched male C57BL/6 wild type (WT) and whole-body SARM1-KO mice were challenged with 16-week diabetic stress initiated by streptozotocin (STZ). SARM1 mRNA or protein levels were suppressed in KO hearts. STZ induced similar hyperglycemia (~600 mg/dL) in both WT and KO mice after 16 weeks. Chronic diabetic stress led to progressive decline in systolic function (FS: 50% vs 35%; P<0.05; n=5) in WT mice, which was ameliorated in KO mice (48%; P<0.05; n=5). Progressive decline in diastolic function by chronic diabetes (E’/A’: 1.53 vs 1.12; n=5) was also improved in diabetic KO mice (1.5; P<0.05; n=5). Up-regulated Nppb in diabetic WT hearts was suppressed by SARM1 deficiency. No compensatory changes in expressions of other NAD hydrolases were observed in diabetic KO hearts. Cardiac fibrosis was induced in diabetic WT hearts and were suppressed in diabetic KO hearts after 16-week diabetic stress. WT and KO mice were challenged with high fat diet feeding (HFD) or HFD with L-NAME (a HFpEF regimen) for 16 weeks. Systolic function was unchanged in mice after HFD or HFpEF regimen, with or without SARM1 deficiency. However, SARM1 deficiency ameliorated diastolic dysfunction of male mice induced by HFD (WT vs KO E’/A’ = 1.07 vs 1.37, n=5) or HFpEF regimen (WT vs KO E’/A’ = 0.96 vs 1.31, n=6). Unlike diabetic cardiomyopathy induced by STZ, cardiac hypertrophy in WT mice was induced by HFD or HFpEF regimen, and KO mice showed decreases in hypertrophy induced by the two stressors.

Conclusion:
Our data support a protective role of SARM1 deficiency in cardiomyopathy. Pathogenic mechanisms of SARM1 in cardiomyopathy induced by metabolic or hypertensive stresses remain to be determined.
Abstract 13327: Development and Validation of a Clinical Risk Score to Predict the Critical Illness in Hospitalized Patients With COVID-19
Authors: Katsouli Anthi , Gazi Sadia , Marfia Paula , Lee Helen , Qazi Sameer , Komorowski Monica , Bertino Ann-Marie , Joshi Neeraj
Published: April 2022

The Covid-19 pandemic has obligated healthcare systems to triage patients efficiently in order to utilize resources in the proper manner. Robust, validated clinical prediction tools are lacking that identify patients with coronavirus disease 2019 who are at the highest risk of mortality.

A cohort of 661 positive COVID patients admitted to the Loyola hospital from 3/11/2020 to 10/12/2020 was used to validate previously published results with the composite outcome of ‘critically ill’, defined as invasive ventilation, ICU admission, or in-hospital death. Epidemiological, clinical, laboratory, and imaging variables ascertained at hospital admission were screened using Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression to construct a predictive risk score. Accuracy of the score was measured by the area under the receiver operating characteristic curve (AUC).

Fifty-two (52) percent of our cohort had critical illness compared to 8% in the Liang paper (the first predictor model which was developed in China). Our population was older, had significantly higher abnormal chest x-ray, dyspnea, and number of comorbidities compared to their population. In addition, our population had higher values for NLR and LDH and lower direct bilirubin. Using the model coefficients presenting in Liang et al, the AUC was only 0.68 (95% CI: 0.64, 0.72), considerably lower than .88 presented in their publication. LASSO variable selection identified 8 variables (HR, SBP, fever, SpO2<90, LDH, ferritin, D dimer, CRP on admission) for a multivariable model. In the multivariable model: SpO2 <90, fever at admission, and increasing LDH were found to be statistically associated with our outcome. We finally added baseline predictors of age, sex, race, and number of comorbidities to the LASSO predictors which resulted in an AUC of 0.75 (95% CI: 0.71, 0.78).

In our study, we found that three predictors (SpO2 <90, fever, and increasing LDH on admission) were selected by the LASSO analysis to construct a predictive nomogram. The application of our model would help clinicians make a prompt decision to optimize patient stratification management. However, this quantitative tool needs to be validated by further large-scale prospective studies.