bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14240: Thoracic Aortic Calcium for the Prediction of Stroke Mortality: The Coronary Artery Calcium Consortium
Authors: Obisesan Olufunmilayo H , Osei Albert D , Berman Daniel , Dardari Zeina , Uddin S M Iftekhar , Dzaye Omar , Orimoloye Olusola A , Budoff Matthew J , Miedema Michael D , Rumberger John A , Mirbolouk Mohammadhassan , Rozanski Alan , Shaw Leslee J , Nasir Khurram , Blaha Michael J
Published: May 2021

Introduction:
Thoracic aortic calcium(TAC) is an important marker of extra-coronary atherosclerosis with known predictive value for all-cause mortality. We sought to explore the predictive value of TAC for stroke mortality, independent of the more established coronary artery calcium score.

Methods:
The Coronary Artery Calcium(CAC) Consortium is a retrospectively assembled database of 66,636 patients aged ≥18 years with no prior history of cardiovascular disease, who had CAC scans done for risk stratification and were followed-up for an average of 12±4years. CAC scans capture a view of the adjacent thoracic aorta, enabling us to assess TAC at no extra cost. TAC was analyzed as present or not present and we restricted analysis to those with this information available. To account for competing risks for death from other causes, we utilized multivariable-adjusted competing risk regression models adjusted for traditional cardiovascular risk factors (age, sex, hypertension, hyperlipidemia, cigarette smoking, diabetes, family history of CHD) and CAC score. We report the relationship between TAC and stroke mortality using sub-distribution hazard ratios(SHR) with 95% CI.

Results:
There were 41,066 patients with information on TAC, 110 of whom had stroke mortality. The mean age of participants was 53.8±10.3 years, with 34.4% female. The unadjusted SHR for stroke mortality among those who had TAC compared to those who did not was 8.80(95%CI:5.97,12.98). After adjusting for traditional risk factors and CAC score, the SHR was 2.21(95%CI:1.39,3.49). The fully adjusted SHR for females was 3.42(95%CI:1.74,6.73) while for males it was 1.55(95%CI:0.83,2.90).

Conclusion:
TAC was predictive of stroke mortality independent of traditional risk factors and CAC, more so in females. The presence of TAC appears to be an independent marker of stroke mortality risk though further research is needed to study its incremental value over existing cardiovascular risk prediction models.
Abstract 14255: Contemporary Characteristics and Management of Patients Aged ≥ 80 Years Presenting With Non-ST Elevation Myocardial Infarctions in the United States: A Nationwide Inpatient Sample Cohort Study
Authors: Igbinomwanhia Efehi , Sanchez Nadales Alejandro , Grimm Richard A , Griffin Brian P , Kapadia Samir R , Xu Bo
Published: May 2021

Introduction:
Improvements in primary prevention, medical therapies and interventions have coincided with a rapidly aging population across the globe. The contemporary characteristics and in-hospital outcomes of non-ST-elevation myocardial infarction (NSTEMI) among patients ≥ 80 years old in the United States (US) are not well studied.

Methods:
Adults (≥ 18) with a primary discharge diagnosis of NSTEMI were identified from the 2016 National Inpatient Sample. The exposure of interest was age ≥80 years, with a comparison group of those aged between 18 and 79 years.

Results:
Of 93,875 patients who had NSTEMI, 22,210 (23.65%) were ≥ 80 years. Among patients ≥ 80 years, 52.5% were female, 73.6% were Caucasians, with a significant proportion being managed by conservative therapy (73.4%). Patients ≥ 80 years were less likely to receive percutaneous coronary intervention (PCI) (adjusted odds ratio [aOR]: 0.49; 95% confidence intervals [CI]: 0.47-0.51) or coronary artery bypass graft surgery (CABG) (aOR: 0.28; 95% CI: 0.25-0.30) when compared to the younger group. Regardless of management strategy, patients ≥ 80 years old had higher inpatient mortality compared to younger patients. Patients ≥ 80 years undergoing PCI experienced more complete heart block, but not other complications, such as cardiogenic shock, cardiac arrest, and stroke, compared to the younger group (Table). NSTEMI patients ≥ 80 years who were managed conservatively or by CABG had a higher Elixhauser comorbidity index than patients undergoing PCI.

Conclusions:
A significant number of NSTEMI patients in the US were aged ≥ 80 years. Despite overall similar in-hospital complications profiles across management strategies, NSTEMI in patients ≥ 80 years was most often managed conservatively.
Abstract 14262: Atrial Fibrillation Burden and Clinical Outcomes in Patients With Cardiac Implanted Electronic Devices
Authors: Chew Derek S , Li Zhen , Steinberg Benjamin A , Obrien Emily C , Pritchard Jessica , Bunch T Jared J , Mark Daniel B , Greiner Melissa , Piccini Jonathan P
Published: May 2021

Introduction:
The relationship between atrial fibrillation (AF) burden and the risk of adverse outcomes is incompletely understood.

Methods:
In a longitudinal cohort study of patients with a clinical history of non-permanent AF who underwent a new implantation of an Abbott cardiac implantable electronic device (CIED) between 2010 and 2016, we linked Merlin.net
TM
remote-monitoring data with Medicare claims to assess the association between device-detected AF burden (daily percentage in AF) and outcomes of all-cause mortality, all-cause hospitalization, cardiovascular (CV) hospitalization, or ischemic stroke over 1-year of follow up via Kaplan-Meier estimates, cumulative incidence function and Cox proportional hazards modeling.

Results:
Among 39,710 AF patients with
de novo
CIEDs, the median age was 77.1±8.7 years, 60.7% were male, and the mean CHA
2
DS
2
-VASc score was 4.9±1.3. Over the 1-year follow up period, there were 3,523 (cumulative incidence of 9%) deaths, 446 (1.1%) ischemic strokes, 15,736 (40%) hospitalizations, and 11,869 (30%) CV-related hospitalizations. Increasing AF burden (per 10 percentage points) was significantly associated with an increased risk of all-cause mortality (hazard ratio (HR) 1.06, 95% confidence interval 1.05-1.08), all-cause hospitalization (HR 1.04, 95% CI 1.03, 1.05), CV hospitalization (HR 1.04, 95% CI 1.03-1.05) and ischemic stroke (HR 1.05, 95% CI 1.01-1.10). There was a similar direction in these outcome associations when AF burden was analyzed as a categorical variable
(Figure)
or using an alternate definition of AF burden (maximum single-episode AF duration).

Conclusions:
Among older patients with non-permanent AF, there is an exposure-response relationship between AF burden and adverse outcomes. These data suggest that early intervention and CV risk factor modification aimed at slowing the progression of AF may reduce long term AF-related adverse CV outcomes.
Abstract 14283: Coronary Microvascular Function is Correlated With Peak Exercise Capacity in Patients With Unexplained Cardiac Exertion Symptoms and Non-obstructive Coronary Artery Disease
Authors: Ahmad Ali , Corban Michel , Toya Takumi , Verbrugge Frederik H , Sara Jaskanwal D , Ozcan Ilke , Lerman Lilach O , Borlaug Barry A , LERMAN Amir
Published: May 2021

Introduction:
Coronary microvascular dysfunction (CMD) is prevalent in symptomatic patients with no obstructive coronary artery disease. We postulated that exercise capacity and cardiac output augmentation in response to exercise are linked to coronary microvascular function in this patient population.

Methods:
Fifty-one consecutive patients with unexplained cardiac exertion symptoms, non-obstructive coronary artery disease on angiography (<50% stenosis), and normal left ventricular ejection fraction (>50%) who underwent concurrent clinically indicated coronary reactivity testing and invasive cardiopulmonary exercise testing (CPEX) were included. Microvascular function was assessed by coronary flow reserve (CFR; hyperemic/resting flow) in response to intracoronary adenosine injection. Cardiac output (CO) was calculated at rest and peak exercise using Fick’s formula. CO limitation was defined as a measured (peak CO - resting CO) <80% than the expected [6*absolute ΔVO
2
(Peak VO
2
-Rest VO
2
) increase in CO in L/min]. The relationship between CFR, maximal exercise capacity, and CO augmentation at peak exercise was explored.

Results:
Patients were 56.6±10.5 years old and 73% were females. CFR had a modest positive correlation with measured increase in CO (r=0.42; P=0.003) (
Fig 1A
), and with maximal ergometric exercise capacity [in Watts/Kg] (Pearson’s r=0.33, P=0.02) (
Fig 1B
). Patients with, vs. without impaired cardiac limitations during exercise, had significantly lower CFR levels (2.6±0.5 vs 3.1±0.7; P=0.01) (
Fig 2
).

Conclusion:
Impaired coronary microvascular function is associated with lower peak exercise capacity and reduced cardiac output augmentation in response to exercise, underscoring the functional ramification of CMD in symptomatic patients.
Abstract 14287: Iron Deficiency is Associated With More Severe Pulmonary Vascular Disease in Pulmonary Hypertension Due to Chronic Lung Disease
Authors: Tatah Jasmine , Pritzker Marc R , Thenappan Thenappan , Prins Kurt W
Published: May 2021

Background:
Iron deficiency promotes pulmonary vascular remodeling in pre-clinical models, and is associated with worse outcomes in pulmonary arterial hypertension. However, the consequences of iron deficiency in patients with pulmonary hypertension due to chronic lung disease (Group 3 PH) are unexplored.

Methods:
We studied 122 consecutive Group 3 PH patients from the University of Minnesota Pulmonary Hypertension Repository. Serum soluble transferrin receptor (sTR) levels quantified iron deficiency. We evaluated the relationship between iron deficiency and pulmonary vascular disease, right ventricular (RV) function, exercise capacity, and survival.

Results:
The iron deficient group (<4.8mg/L sTR) had significantly higher mean pulmonary arterial pressure (40±9 mmHg, n=59 vs. 44±13 mmHg, n=61;
p
=.02) and lower pulmonary arterial compliance (2.2±1.2 mL/mmHg, n=52 vs. 1.7±0.8 mL/mmHg, n=55;
p
=.01), but there was no difference in pulmonary vascular resistance. Moreover, there were trends for higher right atrial pressure (7±4 mmHg, n=58 vs. 9±6 mmHg, n=61;
p
=0.08) in iron deficient patients. However, iron deficiency did not significantly alter RV function by echocardiography, 6-minute walk distance, or survival.

Conclusions:
Iron deficiency in Group 3 PH is associated with worse pulmonary vascular disease. This suggests iron deficiency could contribute to pulmonary vascular disease in Group 3 PH, and future studies are needed to determine if iron replacement could be a therapy for this deadly type of PH.
Abstract 14298: Right Ventricular Strain Before and After Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension
Authors: Wong Darrin , Tigges Averie , Ang Lawrence , PATEL MITUL , Kim Hyong , Poch David , Raisinghani Ajit , Madani Michael M , Demaria Anthony N , Mahmud Ehtisham , Blanchard Daniel G
Published: May 2021

Background:
Right ventricular (RV) function is impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be an alternative treatment for patients (pts) who are not candidates for pulmonary thromboendarterectomy (PTE). We assessed the RV global and segmental strain patterns in pts who underwent BPA.

Methods:
Between 12/2016 and 5/2019, 22 pts had completed BPA treatment and had transthoracic echocardiograms (echos) before and after treatment. Of those 22 pts, 14 had echos with adequate imaging of the RV. Epsilon EchoInsight® was used to measure global and segmental RV strain. Tricuspid annular plane excursion (TAPSE) was also measured. Paired t-tests were used to determine mean differences for pre & post BPA, and Pearson correlation coefficient was used to determine association with hemodynamics.

Results:
RV global longitudinal strain (GLS) significantly improved after BPA (-11.1±3.4 to -16.2±2.9 % p<0.05). The apical and mid segmental strain also significantly improved after BPA (-5.0±9.1 to -12.5±7.5%, p=0.03; -13.3±6.2 to -17.5±5.4%, p<0.01 respectively). Basal strain did not significantly change (-15.2±6.3 to -18.5±9.2%, p=0.22). Furthermore, TAPSE did not change significantly (1.87±0.5 to 1.95±0.5 cm, p=0.55). Hemodynamically, mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) significantly decreased (40.3±10.5 to 34.0±10.3 mmHg, p=0.001 and 5.9±3.1 to 3.9±1.8 WU, p=0.01) while cardiac output remained unchanged (5.6±2.0 to 5.7±1.1 L/min, p=0.86). There was no correlation between improvement in RV GLS and decrease in mPAP and PVR.

Conclusion:
RV function as measured by RV GLS significantly improved after BPA, though only the mid and apical segments improved. TAPSE and RV basal strain did not change after BPA. Previous studies have shown that GLS did not improve significantly after PTE. Furthermore, TAPSE significantly decreases after PTE. The reasons for the difference in RV function after PTE vs BPA are not entirely clear, but may be due to operability and location of disease, as well as immediate post-operative RV stunning after PTE.
Abstract 14302: Adoption of Sacubitril/Valsartan to Treat Acute Decompensated Heart Failure Improves Health System Finances Under Value-based Alternative Payment Models
Authors: Shafrin Jason , Aliyev Elmar R , Brauer Michelle , Park Siyeon , Shen Xian
Published: May 2021

Introduction:
The PIONEER-HF trial demonstrated superior efficacy of sacubitril/valsartan over the angiotensin-converting-enzyme inhibitor (ACEi) enalapril in treating patients with acute decompensated heart failure (ADHF) after stabilization in the inpatient setting, but how medication choice affects health system finances is unknown. Measuring the financial impact is complicated as health systems are increasingly reimbursed through value-based alternative payment models (APM).

Methods:
A decision tree model was used to assess the financial impact of health system adoption of sacubitril/valsartan to treat ADHF under APM reimbursement. The model estimated differences in health care utilization and cost when treating hospitalized ADHF patients with ACEi or angiotensin-receptor blockers compared to sacubitril/valsartan using efficacy results from PIONEER-HF. The financial impact on health systems was assessed across three common APMs: Medicare Shared Savings Program (MSSP), Bundled Payments for Care Improvement (BPCI), and fee-for-service payments adjusted via the Hospital Readmission Reduction Program (HRRP).

Results:
Sacubitril/valsartan reduced re-hospitalizations after an ADHF admission by 46.3% for individuals aged 18-64 years and 23.4% for individuals aged ≥65 years. Health system financial benefit from adopting sacubitril/valsartan was $740 per ADHF case per year (PCPY). Savings were larger for patients aged ≥65 years ($803 PCPY) compared to those <65 years ($653 PCPY). Adoption of sacubitril/valsartan improved health system finances under value-based APMs with the largest financial benefits under the HRRP ($1,190 financial gain PCPY), followed by BPCI ($645 financial gain PCPY) and MSSP ($253 financial gain PCPY).

Conclusions:
Adoption of sacubitril/valsartan to treat ADHF is expected to decrease hospitalizations and lead to a positive net financial impact on health systems under the commonly implemented APMs.
Abstract 14308: Integrative Epigenomic Analysis Identifies Enhancer Modifying Variants Linked to Cardiomyopathy Genes
Authors: Gacita Anthony M , Fullenkamp Dominic , Ohiri Joyce C , Pottinger Tess , Puckelwartz Megan , Nobrega Marcello A , McNally Elizabeth M
Published: May 2021

Introduction:
Inherited cardiomyopathy is caused by mutations in more than 100 genes. A well-recognized clinical feature of genetic cardiomyopathy is varying phenotypic expression. Even with identical primary mutations, there is a range of clinical outcomes. Genetic variants in protein coding regions have been shown to alter the phenotypic expression of primary cardiomyopathy-causing mutations. However, the contribution of noncoding variation has been less well studied.

Methods and Results:
We used an integrative analysis of >20 publicly-available heart enhancer function and enhancer target datasets to identify genomic regions predicted to regulate the cardiomyopathy genes,
MYH7
and
LMNA
. We identified two candidate enhancer clusters around the
MYH7
gene and three clusters around the
LMNA
gene. We tested enhancers in these clusters using reporter assays and CRISPr-mediated deletion in human cardiomyocytes derived from induced pluripotent stem cells (iCMs). We identified a super enhancer upstream of
MYH7
that is necessary for high
MYH7
expression in iCMs. These regulatory regions contained sequence variants within transcription factor binding sites that altered enhancer function. We created an informatic pipeline that extended this strategy genomewide to identify an additional enhancer modifying variant upstream of
MYH7
. This variant disrupts a transcription factor binding site upstream of
MYH7
and limits
MYH7
upregulation. We extended these analyses by examining clinical correlates, finding that this variant correlated with a more dilated left ventricle over time in patients with cardiomyopathy.

Conclusions:
We identified two enhancer regions important for
MYH7
expression in iCMs. These enhancer regions may be utilized to induce
MYH7
during human development and heart failure.
MYH7
changes in heart failure have been linked to cardiomyopathy phenotypes. The variant upstream of
MYH7
likely alters these changes and results in a more severe phenotype. These findings demonstrate that noncoding variants have clinical utility and targeted assessment of noncoding modifiers may become integrated into clinical care.
Abstract 14322: The Relationship Between Self-care and Health-related Quality Life in Patients With Heart Failure Differs by Age
Authors: Lee Kyoung Suk , Jung Mi Sook
Published: May 2021

Background:
Although poor self-care is expected to negatively influence health-related quality of life (HRQOL), this relationship is not consistent. The possible reason might be related that older people reconceptualize or change their expectations for HRQOL. Therefore, vigilant monitoring daily symptom status and other self-care activity might not benefit for older patients with HF to improve their HRQOL.

Objective:
To examine whether the relationship between self-care and HRQOL differs between younger (age <65 years) and older patients (age≥65 years) with HF.

Methods:
A total of 138 patients were included in this study (60 years, 29% female, 12.3% NYHA functional class III/IV). Patients were asked to complete the Kansas City Cardiomyopathy Questionnaire and the self-care maintenance of the Self-care HF index to measure overall HRQOL and self-care maintenance. To examine the association between self-care maintenance and HRQOL in younger and older patients, two separate linear regressions were performed after controlling for covariates (age, gender, marital status, NYHA functional class, perceived control, and social support).

Results:
Self-care maintenance and overall HRQOL were not different between younger (n=90) and older patients (n=48). However, self-care maintenance was an independent predictor of overall HRQOL in only older patients, but not their younger counterparts. In older patients, better self-care maintenance was associated with poorer overall HRQOL (β=-0.37, p=0.03).

Conclusions:
We found that the relationship between self-care and HRQOL is different between younger and older patients with HF. This finding indicates that improving self-care alone does not necessarily improve HRQOL in older patients so that interventions aimed to enhance HRQOL in older patients need to include strategies considering older patients’ conceptualization for HRQOL.
Abstract 14338: Prevalence, Associations and Outcomes of Double Orifice and Parachute Mitral Valve
Authors: obiaka uzoma , Chow Anna , Yau Jen Lie , Matto Morina Valeria , Srivastava Shubhika
Published: May 2021

Background:
The incidence of congenital mitral valve disease is 0.4%; Double Orifice Mitral Valve (DOMV) and Parachute Mitral Valve (PMV) are two morphologic pathologies that may result in mitral valve dysfunction. The objectives of this study are 1) To describe valve function and progression and 2) To define factors contributing to disease progression.

Methods:
Retrospective database review. Fyler codes for DOMV, PMV and text search was performed. Echocardiographic images, echo reports, and chart review were used to identify mitral regurgitation (MR), mitral stenosis (MS), morphology, and associated lesions.

Results:
39 patients with DOMV and 76 patients with PMV were identified. In the DOMV cohort, 51% were male, median age at diagnosis was 0.17 years (IQR 0.01, 3.88); median follow-up of 5.92 years (IQR 0.46, 10.22). In the PMV cohort, 44% were male, median age at diagnosis at was 0.01 years (IQR 0, 0.34); median follow-up of 2.56 years (IQR 0.25, 9.55). 41% of DOMV and 23% of patients with PMV had normal valve function at initial visit. DOMV was associated with MR (p=0.04), and PMV with MS (p<0.0001). 23% of patients in the PMV cohort had progressive MS compared to 5% of patients in the DOMV cohort (p<0.0001). There was no significant difference in MR progression between both groups (p=0.02). Papillary muscle (PM) morphology was evaluated in 37 (excluding canals) of 76 patients in the PMV cohort. 5 had true PMV (single PM), 32 had variant PMV with two PM groups of which 62.5% had dominant posterior medial PM. 67% of those with posterior medial PM dominance had progressive MS irrespective of association with Shone’s complex. The anterolateral PM muscle group dominant PMV were not associated with Shone’s complex and progressive MS.

Conclusion:
DOMV are more likely to have MR while PMV are more likely to have MS. DOMV has non progressive MR and MS. Posterior medial PM dominance in PMV is more likely to have progressive MS.
Abstract 14354: Persistence to Oral Anticoagulation Treatment in Non-valvular Atrial Fibrillation Patients in the United States
Authors: Dhamane Amol , Di Fusco Manuela , Gutierrez Cynthia , Ferri Mauricio , Russ Cristina , Tsai Wan-Lun , Emir Birol , Keshishian Allison
Published: May 2021

Background:
Studies have shown that nonvalvular atrial fibrillation (NVAF) patients who discontinue direct oral anticoagulants (DOAC) are at higher risk of complications, such as stroke. This analysis compared the risk of non-persistence of OACs among NVAF patients.

Methods:
Adult NVAF patients who initiated apixaban, dabigatran, rivaroxaban, or warfarin were identified using 01JAN2013-31MAR2019 data from the IQVIA commercial claims database. Non-persistence was defined as discontinuation (no evidence of index OAC use for 60 days from the last days’ of supply) or switch to another OAC. Kaplan-Meier (KM) curves were generated to illustrate time-to-non-persistence along with cumulative incidences of non-persistence. Adjusted cox proportional hazards models, including time-varying covariates (e.g., major bleeding, stroke), were used to evaluate non-persistence risk.

Results:
A total of 32,103 apixaban, 5,906 dabigatran, 29,385 rivaroxaban, and 21,420 warfarin patients were included; mean age: 63. Apixaban was associated with a lower risk of non-persistence compared to dabigatran (hazard ratio [HR]: 0.54; 95% confidence interval [CI]: 0.52-0.56), rivaroxaban (HR: 0.79; 95% CI: 0.78-0.81), and warfarin (HR: 0.66; 95% CI: 0.65-0.68). Dabigatran was associated with a higher risk of non-persistence compared to warfarin (HR: 1.23; 95% CI: 1.19-1.28) and rivaroxaban (HR: 1.47; 95% CI: 1.42-1.52), and rivaroxaban was associated with a lower risk compared to warfarin (HR: 0.84; 95% CI: 0.82-0.86). KM curves and cumulative incidences are presented below (Figure).

Conclusions:
In this group of NVAF patients, apixaban was associated with a significantly lower risk of non-persistence compared to dabigatran, rivaroxaban, and warfarin. Rivaroxaban was associated with a lower risk of non-persistence compared to warfarin and dabigatran. Such differences are critical as persistence with OACs is essential to prevent thromboembolic complications.
Abstract 14358: Treadmill Exercise Testing Improves Diagnostic Accuracy in Children With Concealed Congenital Long QT Syndrome
Authors: Patel Trisha , Kamande Stanley , Jarosz Elizabeth , Bost James , hanumanthaiah Sridhar , Berul Charles I , Sherwin Elizabeth D , Moak Jeffrey P
Published: May 2021

Introduction:
Resting electrocardiogram (ECG) identification of long QT syndrome (LQTS) has limitations. Uncertainty exists on how to classify patients with borderline prolonged QT intervals. We tested if exercise testing could help serve as a guide for which children with borderline prolonged QT intervals may be gene positive for LQTS.

Methods:
Pediatric patients (n=139) were divided into three groups: Controls (n=76), gene positive LQTS with borderline QTc (n=21), and gene negative patients with borderline QTc (n=42). Borderline QTc was defined between 440 to 470 (male) and 440 to 480 (female) msec. ECGs were recorded while supine, sitting, and standing. Patients then underwent treadmill stress testing using the Bruce protocol followed by a 9-minute recovery phase. Statistical analysis was completed to compare the QTc intervals amongst all three of the groups using t-test, ANOVA, and the Youden method to calculate sensitivity and specificity cut points.

Results:
Supine resting QTc, age, and Schwartz score for the three groups were: 1) Gene positive: 446 ± 23 msec, 12.4 ± 3.4 yo, 3.2 ± 1.8; 2) Gene negative: 445 ± 20 msec, 12.1 ± 2.8 yo, 2.0 ± 1.2; and 3) Control: 400 ± 24 msec, 15.0 ± 3 yo. The three groups could be differentiated by their QTc response at two time points: standing and recovery phase at six minutes. Standing QTc ≥ 460 msec differentiated borderline prolonged QTc patients (Gene positive and Gene negative) from controls with a specificity of 90% for gene positive versus control and 83% for gene negative versus control. A late recovery QTc ≥ 480 msec at minute six distinguished Gene positive from Gene negative patients with a specificity of >97%.

Conclusions:
Exercise stress testing can be useful to identify Gene positive borderline LQTS from a normal population and Gene negative borderline QTc patients, allowing for increased cost effectiveness by selectively gene testing a higher risk group of patients with borderline QTc intervals and intermediate Schwartz scores.
Abstract 14359: Single Nucleotide Polymorphisms in Genes Involved in L-arginine / Dimethylarginine Metabolism Predispose for Pulmonary Hypertension and Acute Mountain Sickness at High Altitude
Authors: Hannemann Juliane , Zummack Julia , SIQUES PATRICIA , BRITO JULIO , Boeger Rainer
Published: May 2021

Introduction:
Chronic (CH) and chronic-intermittent (CIH) exposure to hypoxia at high altitude causes acute or chronic mountain sickness and elevation of mean pulmonary arterial pressure (mPAP). This is paralleled by increased plasma levels of ADMA, an endogenous inhibitor of NO synthesis. ADMA is cleaved by dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), whilst symmetric dimethylarginine (SDMA) is cleaved by AGXT2. Arginase (ARG1 and ARG2) competes with endothelial NO synthase (NOS3) for L-arginine as substrate. We have shown previously that baseline ADMA (at sea level) determines mPAP after six months of CIH; cut-off values of 25 mm Hg and 30 mm Hg are being used to diagnose high altitude pulmonary hypertension.

Hypothesis:
We hypothesized that genetic variability in genes coding for core enzymes of ADMA, SDMA, and L-arginine metabolism may predispose individuals for high altitude disease and pulmonary hypertension.

Methods:
We genotyped 16 common single nucleotide polymorphisms in the NOS3, DDAH1, DDAH2, AGXT2, ARG1 and ARG2 genes of 69 healthy male Chilean subjects. Study participants adhered to a CIH regimen (5d at 3,550m, 2d at sea level) for six months. Metabolites were measured by LC-MS/MS; mPAP was estimated by echocardiography at six months, and altitude acclimatization was assessed by Lake Louise Score and arterial oxygen saturation.

Results:
Carriers of the minor allele of DDAH1 rs233112 had a higher mean baseline ADMA level (0.76±0.03 vs. 0.67±0.02 μmol/l; p<0.05), whilst the major allele of DDAH2 rs805304 was linked to an exacerbated increase of ADMA in hypoxia (0.10±0.03 vs. 0.04±0.04 μmol/l; p<0.02). Study participants carrying the minor allele of ARG1 rs2781667 had a relative risk of elevated mPAP (>25 mm Hg) of 1.70 (1.56-1.85; p<0.0001), and carriers of the minor allele of NOS3 rs2070744 had a relative risk of elevated mPAP (>30 mm Hg) of 1.58 (1.47-1.69; p<0.0001). The NOS3 and DDAH2 genes were associated with the incidence of acute mountain sickness.

Conclusions:
We conclude that genetic variability in the L-arginine / ADMA / NO pathway is an important determinant of high altitude pulmonary hypertension and acute mountain sickness. DDAH1 is linked to baseline ADMA, whilst DDAH2 determines the response of ADMA to hypoxia.
Abstract 14362: Shifting Trends in Timing of Pacemaker Implantation After Transcatheter Aortic Valve Replacement
Authors: Mazzella Anthony , Hendrickson Michael , Arora Sameer , Sanders Mason , Li Quefeng , Vavalle John , Gehi Anil
Published: May 2021

Introduction:
Hospital length of stay with transcatheter aortic valve replacements (TAVRs) has decreased, though the rate of heart block requiring permanent pacemaker (PPM) implantation after TAVR has remained steady. It is unknown whether more patients are being readmitted for PPM after discharge from TAVR.

Objective:
To explore frequency, timing, and risk factors for PPM implant after TAVR in a nationally representative database.

Methods:
Patients who underwent TAVR from January 2012 through December 2017 were identified in the Nationwide Readmissions Database (NRD). Smoothing splines and logistic regression were used to analyze trends in length of stay and timing of PPM implantation after TAVR respectively. Multivariable logistic regression analysis was performed to identify risk factors for overall, early (during index hospitalization), and late (during subsequent hospitalization) PPM after TAVR.

Results:
Of the 62,083 included, 6,817 (11.0%) underwent PPM implantation [6,137 (9.9%) early and 680 (1.1%) late]. Rates of PPM remained stable between 8% and 12.5% with an increasing proportion occurring late (7% in 2012 increasing to 13% in 2017, p < 0.0001 for trend) (Figure 1). Late PPM was associated with atrial fibrillation (p < 0.01), diabetes mellitus (p < 0.001), chronic kidney disease (p < 0.05), second degree AVB (p < 0.001), left bundle branch block (p < 0.001), right bundle branch block (p < 0.001), and bifascicular block (p < 0.001).

Conclusions:
There has been a significant increase in the proportion of patients requiring readmission for PPM implantation after TAVR. As this high-risk population grows, algorithms for extended in-hospital observation or ambulatory cardiac monitoring post-TAVR are needed to reduce the risk for adverse events.
Abstract 14363: Clustering of Multiple Cardiometabolic Risk Factors by Race/Ethnicity and Age
Authors: Kizzee Olivia P , Lo Joan C
Published: May 2021

Introduction:
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death among Americans. The burden of cardiometabolic risk factor clustering in ethnic subgroups is not well described for US Asians compared to other race/ethnicities.

Methods:
This cross-sectional study was conducted using electronic health data for White (N=634,200), Black (N=85,156), Hispanic (N=188,071), Filipino (N=78,000) and Chinese (N=72,545) Kaiser Permanente Northern California health plan members in 2016 who were aged 40-84y and had weight status assessed. We examined the proportions of men and women in each racial/ethnic group with clustered cardiometabolic risks (CCR), defined as having diabetes, hypertension, and obesity. Diabetes mellitus (DM) was based on a clinical DM diagnosis, lab criteria, or receipt of DM pharmacotherapy. Hypertension was defined by clinical diagnosis. Obesity was characterized by WHO standard (BMI ≥30 kg/m
2
) and Asian-specific (BMI ≥27.5 kg/m
2
) thresholds.

Results:
CCR prevalence varied by race/ethnicity, age, and the BMI criteria used for obesity (standard or Asian threshold). Use of the Asian threshold resulted in Filipinos having CCR prevalence that approached Blacks and Hispanics across all age groups (Figure). The Asian criterion nearly doubled the proportion of at-risk Filipinos, particularly older adults aged 65-84y. Filipinos had more than 2x higher CCR prevalence compared to Chinese. Among all ethnic groups except for Blacks, men were more likely than women to have CCR.

Conclusion:
Using an Asian-specific BMI obesity threshold, Filipino-Americans have a higher prevalence of cardiometabolic risk factor clustering than Chinese-Americans, resembling that of Blacks and Hispanics. Identifying Asian ethnicity in electronic health records could help facilitate earlier metabolic assessment and management to further reduce CVD burden, which may be especially important for men.
Abstract 14379: Implementation of Pharmacist-led Antithrombotic Medication Management for Elective Endoscopic Procedures
Authors: Han Henry , Sippola Emily , Chen Wilson , Morgan Spencer , Renner Elizabeth , Ruff Allison , Sales Anne , Kurlander Jacob , Barnes Geoffrey D
Published: May 2021

Introduction:
Mismanagement of antithrombotic medications often leads to cancelled elective procedures. Pharmacist-led anticoagulation management prior to elective procedures is not well studied.

Methods:
We implemented a best practice advisory (BPA) that offered referral to a pharmacist-led medication management service prior to elective outpatient gastrointestinal endoscopies. Eligible patients were taking warfarin, a direct oral anticoagulant, and/or a P2Y12 inhibitor for management of atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease (CAD), peripheral arterial disease (PAD), and/or mechanical heart valve. Patients referred to the antithrombotic service were compared to those managed by the ordering provider. Outcomes assessed included documentation of a medication management plan, guideline-appropriateness of drug cessation prior to endoscopy, and guideline-appropriate rates of enoxaparin bridging for high risk warfarin patients.

Results:
Seventy-four percent of patients (448/645) were referred to the antithrombotic service. These patients were more likely to have had VTE (33.0% vs. 18.2%), less likely to have CAD (31.9% vs. 40.9%; p=0.009 for indication category), and more likely to be prescribed warfarin (32.8% vs 20.9%, p<0.001). After adjusting for baseline differences, patients referred to the antithrombotic service were more likely to have had pre-procedure medication plan documentation (98.7% vs 56.1%, p <0.001), and pre-procedure antithrombotic management was more likely to follow guidelines (97.5% vs. 91.5%, p=0.024). Guideline-appropriate use of bridging enoxaparin for warfarin patients was not different (10/16 [62.5%] vs. 2/6 [33.3%], p=0.221).

Conclusion:
Pre-procedural antithrombotic medication management by a pharmacist-led team for elective endoscopies was associated with more guideline-adherent management and better documentation of the medication plans.
Abstract 14395: Abnormal Regulation of P53-mTOR Pathway by MRNA-binding Protein ZFP36L2 in Peri-partum Cardiomyopathy
Authors: Tatekoshi Yuki , Kouzu Hidemichi , Chang Hsiang-Chun , Shapiro Jason S , Jesus Adam D , McGee Warren A , Ben-Sahra Issam , Chun Chunlei , Ardehali Hossein
Published: May 2021

Introduction:
A loss of function mutation in the mRNA binding protein ZFP36L2 has been associated with congenital heart diseases in humans, although the mechanism remains unclear.

Objectives:
We sought to elucidate the role of ZFP36L2 in the heart using mice with cardiac-specific ZFP36L2 deletion.

Results:
Cardiac-specific
Zfp36l2
knockout (cs-L2KO) female mice exhibit a dramatic phenotype in which the majority of mice die after repeated pregnancies due to heart failure. We performed RNA-seq in H9c2 cells with ZFP36L2 KD, and found the expression of multiple mTOR pathway genes were altered, including marked repression of
Redd1
and
Sesn2
. Consistent with the RNA-seq data, the activity of mTORC1 was increased in cs-L2KO mouse hearts and in ZFP36L2 KD H9c2 cells. Loss of TSC2 mitigated mTORC1 hyperactivity in ZFP36L2 KD cells, indicating that ZFP36L2 regulates mTORC1 activity through the TSC2 complex. Overexpression of REDD1 rescued increased mTORC1 activity with ZFP36L2 KD, suggesting that ZFP36L2 regulates mTORC1, in-part through REDD1. Under total amino acid starvation, we observed higher p-S6K
T389
levels in ZFP36L2 KD cells, and SESN2 overexpression mitigated p-S6K
T389
, indicating loss of ZFP36L2 also regulates mTORC1 through amino acid sensing. p53 is a transcriptional activator of both REDD1 and SESN2, and we found that ZFP36L2 was required to maintain p53 levels by directly destabilizing MDM2 mRNA. Accordingly, administration of Nutlin3, an MDM2 inhibitor, reversed the reduction in p53, REDD1 and SESN2 protein levels, and prevented the increase in S6K phosphorylation in response to ZFP36L2 KD. Next, we treated pregnant mice with rapamycin, and cs-L2KO mice treated with rapamycin displayed significantly improved cardiac function after delivery. Finally, we analyzed human heart samples from patients with peri-partum cardiomyopathy and found ZFP36L2 protein to be significantly decreased and p-S6K
T389
levels increased, compared to healthy controls.

Conclusions:
Our studies demonstrate that ZFP36L2 regulates mTORC1 activity through modifying p53 stability, and that the disruption of this pathway induces peri-partum cardiomyopathy. Inhibition of mTORC1 hyperactivity with rapamycin can be a potential therapy for this disease.
Abstract 14397: Sotatercept Analog RAP-011 Inhibits Right Ventricular Remodeling and Restores Function in a Mouse Model of Pressure Overload
Authors: Joshi Sachindra R , Liu Jun , Pearsall R. Scott , Andre Patrick , Li Gang , Ravindra Kumar
Published: May 2021

IIntroduction:
Right ventricular (RV) failure is the primary cause of death in patients with pulmonary arterial hypertension (PAH). Beneficial effects of sotatercept - an activin receptor type IIA-Fc fusion protein that traps activins and growth differentiation factors - have been reported in PAH patients treated with standard-of-care therapies in a recent phase 2 study (PULSAR). We have reported that therapeutic treatment with sotatercept analog RAP-011 reverses RV remodeling and function in rats with severe angio-obliterative PAH, providing benefits on top of standard care.

Hypothesis:
To determine whether RAP-011 exerts a direct cardioprotective effect in a mouse model of pressure overload-induced RV failure.

Methods:
RV failure was induced in male C57BL/6 mice by pulmonary artery banding (PAB). RAP-011 or vehicle were administered subcutaneously twice weekly for 3 weeks beginning one day post surgery. RV remodeling and function were assessed by echocardiography and RV pressure measured by catheterization. RV fibrosis was assessed by Masson’s trichrome staining.

Results:
PAB caused RV hypertrophy and increased RV wall thickness in comparison to sham surgery. RAP-011 treatment markedly attenuated these PAB-induced changes (by 72% and 41%, respectively; P < 0.0001). PAB significantly reduced tricuspid annular plane systolic excursion (0.68 ± 0.03 vs. 0.98 ± 0.03 mm), which was partially restored by RAP-011 (0.84 ± 0.04 mm; P < 0.01). In addition, the PAB-induced increase in myocardial performance index was reversed by RAP-011 (1.86 vs. 1.48, P < 0.0001). RAP-011 attenuated PAB-induced RV developed pressure (by 82%, P < 0.0001) and partially normalized peak rates of RV pressure change (+dP/dt
max
and -dP/dt
min
, P < 0.05). RAP-011 also reduced the extent of PAB-induced RV fibrosis (19.5% vs. 10.5%, P < 0.001).

Conclusions:
Consistent with our previous findings in a rat model of severe angio-obliterative PAH, RAP-011 treatment reduces RV remodeling and improves function in a PAB model, thus implicating direct cardioprotective actions of RAP-011 as an important component of its therapeutic effects in severe experimental PAH.
Abstract 14409: TRPA1 Channels Are a Source of Calcium-driven Cellular Mechano-arrhythmogenicity
Authors: Cameron Breanne A , Stoyek Matthew R , Quinn T Alexander
Published: May 2021

Introduction:
Pathologic changes in myocardial mechanics and hemodynamic load result in arrhythmias
via
mechanically-induced changes in electrophysiology or intracellular Ca
2+
(‘mechano-arrhythmogenicity’). While molecular mechanisms driving mechano-arrhythmogenicity are poorly defined, they are associated with disease-related alterations in voltage-Ca
2+
dynamics.

Objective:
Define mechanisms of mechano-arrhythmogenicity during alterations in voltage-Ca
2+
dynamics in rabbit ventricular myocytes.

Methods:
Rabbit (♀, NZW) LV myocytes were transiently stretched (8-16% change in sarcomere length, 100ms) during diastole or late repolarisation in control or during K
ATP
channel activation (pinacidil). Drugs were used to buffer Ca
2+
(BAPTA), stabilise RyR (dantrolene), non-selectively block stretch-activated channels (streptomycin), or specifically block (HC-030031) or activate (AITC) mechano-sensitive TRPA1 channels. Voltage-Ca
2+
dynamics were simultaneously monitored with fluorescent dyes (di-4-ANBDQPQ, Fluo-5F) and a single camera-optical splitter system and diastolic Ca
2+
was measured using Fura Red.

Results:
Pinacidil caused greater shortening of the AP than Ca
2+
transient (-144±17
vs
-74±11ms;
n
=24 cells,
N
=7 rabbits;
p
<0.001) with no change in cell stiffness or contractility. Stretch during pinacidil application caused arrhythmias in both diastole and late repolarisation (8 and 10% of stretches;
n
=46,
N
=5), which voltage-Ca
2+
imaging revealed were Ca
2+
-driven. Arrhythmias were reduced with BAPTA (3 and 0% of stretches;
p
<0.05), streptomycin (4 and 2%;
p
<0.05), and HC-030031(2 and 1%;
p
<0.01), while dantrolene had no effect (
n
=40,
N
=5 for each). Stretch in diastole during AITC application also caused arrhythmias (15%;
p
<0.001), which were blocked by HC-030031 (4%;
p
<0.001) or BAPTA (3%;
p
<0.001;
n
=40,
N
=5 each). Both AITC and pinacidil caused an increase in diastolic Ca
2+
(112±29 and 78±29% of control; p<0.05), which was reduced by HC-030031 with AITC (26±24%;
p
<0.05), but not with pinacidil (
n
=25,
N
=5 each).

Conclusions:
TRPA1 activation increases mechano-arrhythmogenicity
via
a Ca
2+
-driven mechanism and may represent a novel anti-arrhythmic target in pathologies involving altered cardiac mechanics.
Abstract 14412: Activation of Autophagic Flux Maintains Mitochondrial Homeostasis During Cardiac Ischemia/reperfusion Injury
Authors: Yang Jing , CHO Geoffrey W , He Lihao , Chu Yuxin , He Jin , Ballinger Scott W , Young Martin E , Prabhu Sumanth D , Gillette Thomas G , Hill Joseph A , Xie Min
Published: May 2021

Background and Hypothesis:
Reperfusion injury accounts for ~50% of myocardial infarct size, and clinically efficacious therapies are lacking. Histone deacetylase (HDAC) inhibition enhances cardiomyocyte autophagic activity, mitochondria biogenesis, and blunts ischemia/reperfusion (I/R) injury when given at the time of reperfusion. However, as HDAC inhibition has pleiotropic effects, we will test whether augmentation of autophagic flux using a specific autophagy-inducing peptide, Tat-Beclin (TB), is cardioprotective.

Methods:
8-12-week-old, wild-type, C57BL6 mice were randomized into three groups: vehicle control, Tat-Scrambled (TS) peptide, or Tat-Beclin (TB) peptide. Each group was subjected to I/R surgery (45min ischemia, 24h reperfusion). Infarct size, systolic function, and mitochondrial dynamics were assayed. Cultured neonatal rat ventricular myocytes (NRVMs) were used to test for cardiomyocyte specificity. Conditional cardiomyocyte ATG7 knockout (ATG7 KO) mice and ATG7 knockdown by siRNA in NRVMs were used to evaluate the role of autophagy.

Results:
TB treatment at reperfusion reduced infarct size by 20.1±6.3% (n=23, p<0.02) and improved systolic function. Increased autophagic flux and reduced reactive oxygen species (ROS) were observed in the infarct border zone. The cardioprotective effects of TB were abolished in ATG7 KO mice. TB increased mtDNA content in the border zone significantly. In NRVMs subjected to I/R, TB reduced cell death by 41±6% (n=12, p<0.001), decreased ROS, and increased mtDNA content significantly by ~50%. Moreover, TB promoted expression of PGC1α (a major driver of mitochondrial biogenesis) both in the infarct border zone and NRVMs subjected to I/R by ~40%, and increased levels of mitochondrial dynamics gene transcripts
Drp1, Fis1,
and
MFN1
/
2.
Conversely, ATG7 knockdown in NRVMs and cardiac ATG7 KO abolished the beneficial effects of TB on mitochondria DNA content.

Conclusions:
Autophagic flux is an essential process to mitigate myocardial reperfusion injury acting, at least in part, by inducing PGC1α-mediated mitochondrial biogenesis. Augmentation of autophagic flux may emerge as a viable clinical therapy to reduce reperfusion injury in myocardial infarction.
Abstract 14414: Bioprosthetic Valve Thrombosis: Different Time to Response to Warfarin in Mitral and Aortic Valves
Authors: Naser Jwan A , Ionescu Filip , Egbe Alexander C , Petrescu Ioana , Nkomo Vuyisile T , Pislaru Cristina , Connolly Heidi M , Pellikka Patricia A , Pislaru Sorin V
Published: May 2021

Background:
Warfarin is known to be effective in the treatment of bioprosthetic valve thrombosis (BPVT). However, the time-course of response to anticoagulation has not been fully characterized.

Hypothesis:
We hypothesized that response to warfarin can differ depending on valve position.

Methods:
We retrospectively identified 45 patients with BPVT diagnosis between 2002 and 2019 that involved either the mitral (MV) or the aortic valve (AV) prostheses, all with eventual echocardiographic resolution with warfarin. BPVT involved AV in 26 (57.8%) patients and MV in 19 (42.2%). Mean gradients (MGs) were tracked starting from BPVT diagnosis until recovery, which was defined as MGs decreasing to initial post-implantation MGs, to 50% below MGs at BPVT diagnosis, or to < 20 mmHg in AV and < 5 mmHg in MV. Kaplan Meier analysis was used to compare recovery time between MV and AV. Duration is reported relative to the time of BPVT diagnosis.

Results:
Recovery was faster in MV than in AV patients treated with warfarin, with median time of 3.8 months in the AV and 1.8 months in the MV group, p < 0.001 (Figure 1). At 1 month follow up, 15.4% recovered in AV group and 21.1% in MV, p = 0.605. At 3 months, 38.5% recovered in the AV and 78.9% in the MV, p = 0.009. At 6 months, 57.7% of AV group recovered while 100% recovered in the MV group, p = 0.001. The longest time for recovery was 30 months in 1 AV patient.

Conclusion:
Recovery using warfarin tended to be faster in BPVT involving the MV compared with the AV. In our study, all patients with MV BPVT recovered by 6 months, while this only happened in half the patients with AV BPVT. This suggests that a longer duration of warfarin trial may be needed in the case of AV disease. This might also suggest that the pathogenesis may differ between the two valves.