bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14294: Effect of Atrial Fibrillation on Patient-Reported Outcomes in Heart Failure With Reduced Ejection Fraction: Secondary Analysis of Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure: HF-ACTION Trial
Authors: Elkholey Khaled , Stavrakis Stavros
Published: December 2023

Background:
Atrial fibrillation (AF) and heart failure (HF) both significantly impact morbidity and mortality, and also account for impaired quality of life. Patient-reported outcomes represent the most direct measurement of quality of life, without influence of interpretation by the clinician. We sought to evaluate the effect of AF on patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in patients with HF with reduced ejection fraction (HFrEF) enrolled in HF-ACTION trial.

Methods:
This was an exploratory post-hoc analysis of the HF-ACTION trial. Patients with reported KCCQ at randomization were included in this analysis. KCCQ was collected at randomization, 3, 6, 9, 12, 24, 36 months. Mixed effects regression modeling was used to explore the effect of AF status at the time of randomization on longitudinal changes in the KCCQ- overall symptom score (OSS) over the duration of follow-up. Covariates adjusted for included age, BMI, sex, race, ejection fraction (EF), NYHA class, HF etiology, smoking, revascularization, MI, and use of Beta blockers, Digoxin, Diuretics, or ACEIs/ARBs.

Results:
A total of 2129 patients (mean age 58.5±12.6 years, males 71.9%) with available KCCQ-OSS at baseline were included and AF was prevalent in 443 (20.8%) patients. AF patients were more likely to be older white males and had lower BMI; with higher prevalence of NYHA classes III/IV, prior MI, revascularization, and ischemic etiology for HF. AF Patients had significantly lower KCCQ-OSS at 3 years (59.9±22 vs. 67.6±19.9, p= 0.002) compared to those without AF. There was a significant time by AF status interaction (p=0.045), suggesting that KCC-OSS changed differently overtime based on the AF status.

Conclusion:
Among patients with HFrEF from HF-ACTION trial, prevalent AF at baseline was associated with lower quality of life and lower KCCQ-OSS over 3 years of follow-up, suggested by the significant interaction between AF status and time of follow-up.
Abstract 14312: Comparison of Machine Learning and Conventional Statistical Modeling for Predicting Readmissions Following Acute Heart Failure Hospitalization
Authors: Abdul-Samad Karem , Ma Shihao , Chong Alice , Wang Chloe X , Wang Xuesong , Austin Peter C , Porter Joan , Ross Heather J , WANG BO , Lee Douglas S
Published: December 2023

Introduction:
Developing accurate models for predicting risk of 30-day readmission has been a major healthcare interest. Evidence suggests that models developed using machine learning (ML) may have better discrimination than conventional statistical models (CSM), but the calibration of such models is unclear.

Objectives:
To compare models developed using CSM or ML to predict 30-day readmission for cardiovascular and non-cardiovascular causes in HF patients.

Methods:
We studied 10,919 patients with HF (> 18 years) discharged alive from a hospital or emergency department (2004-2007) in Ontario, Canada, linked to administrative databases for hospitalization and vital status resulting in complete follow-up. The study sample was randomly divided into training and validation sets in a 2:1 ratio. CSMs to predict 30-day readmission were developed using Fine-Gray subdistribution hazards regression (treating death as a competing risk), and the ML algorithm employed random survival forests. Models were evaluated in the validation set using both discrimination and calibration metrics.

Results:
In the validation sample of 3602 patients (median age 76 [IQR, 67-82] years, 46.6% females), Random Survival Forests (c-statistic = 0.620) showed similar discrimination to the Fine-Gray competing risk model (c-statistic= 0.621) for 30-day cardiovascular readmission. In contrast, for 30-day non-cardiovascular readmission, the Fine-Gray model (c-statistic= 0.641) slightly outperformed the random survival forests model (c-statistic = 0.632). For both outcomes, The Fine-Gray model displayed better calibration than random survival forests when deciles of observed vs. predicted risks were compared (Panels A-D).

Conclusions:
In HF patients, time-to-event analysis of outcomes using Fine-Gray models had similar discrimination but superior calibration to ML model, highlighting the importance of reporting calibration metrics for ML-based prediction models.
Abstract 14323: Significance of Angio-IMR to Predict Heart Failure Post-TAVI
Authors: Fujita Kosuke
Published: December 2023

Background/Introduction:
The number of transcatheter aortic valve implantation (TAVI) procedures is currently increasing. However, a substantial number of patients suffer from repeated heart failure (HF) after the TAVI procedure. The association between Index of Microvascular Resistance (IMR) and HF is already known, especially in HFpEF.

Purpose:
The aim of this study was to assess the prognostic significance of IMR for HF after TAVI. Method and Result: 120 consecutive patients who underwent coronary angiography (CAG) before undergoing TAVI in our hospital between 2018 and 2021 were included in the analysis. Quantitative Flow Ratio (QFR) analysis was performed for each coronary artery, excluding cases undergoing PCI before or after TAVI. The angiography derived IMR was then obtained from the QFR values. Finally, 65 patients were available for IMR analysis. Of these, 12 were hospitalized or underwent medical intensification for HF exacerbations after TAVI. IMR was significantly higher in patients with HF compared without HF. (73.8 (31 to 121) vs 59.7 (26 to 153), p=0.041) No other significant differences were found in age, QFR values, EF, i-EOA on echocardiography after TAVI, STS score, and BNP values before TAVI. All patients with HF were female.

Conclusion:
It is suggested that angio-derived IMR values before TAVI might be a useful predictor of heart failure after TAVI.
Abstract 14327: Association Between Alcohol Intake and Incidence of Heart Failure With and Without Reduced Ejection Fraction Among Participants of the VA Million Veteran Program
Authors: Elhouderi Eiman , Li Yanping , Nguyen Xuan-Mai T , Joseph Jacob , Gaziano John M , Ivey Kerry , Djousse Luc
Published: December 2023

Introduction:
Little is known about the relation of total alcohol intake and beverage types on risk of heart failure (HF). This study aims to examine the relation between amount of alcohol consumed and type of alcohol with risk for HF including subtypes [heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction] in a large cohort of US Veterans.

Methods:
The study cohort included 329,543 Million Veteran Program participants who completed a baseline and lifestyle survey. Subjects with prevalent HF at baseline and incomplete alcohol information were excluded. Moderate alcohol intake was defined as consuming 12-24 g/day for men and 12g/day for women. We used ICD-9-10 codes and EF to define HFpEF and HFrEF. The associations between alcohol intake, beverage preference, and incidence of HFpEF and HFrEF were assessed using Cox proportional hazard model (CPHM) adjusted for age, sex, race, body mass index, cigarette smoking, education, exercise, diet, baseline prevalence of high cholesterol, hypertension, diabetes mellitus, statin use and atrial fibrillation.

Results:
Mean age was 65 years and 91.4% were men. With mean follow-up of 4.5 years, we observed 20,694 incident HF events (6078 HFrEF and 4531 HFpEF). The CPHM showed J shaped relationship between alcohol consumption and HF risk. Compared to never drinkers, adjusted HRs (95% CI) for HF were 0.89 (0.85, 0.95), 0.85 (0.79,0.91), 0.80 (0.74, 0.86), 0.80 (0.72, 0.88), 0.93 (0.84, 1.04) and 1.03(0.95, 1.12) for categories of current drinkers of ≤6 g/d, >6-12 g/d, >12-24g/d, >24-36g/d, >36-48 g/d and heavy drinking (> 48 g/d)/alcohol use disorder, respectively. We found a similar association pattern between alcohol intake and risk of HFpEF and HFrEF (Fig). There was no difference in alcohol preference and HF risk among light and moderate drinkers.

Conclusion:
Light to moderate alcohol consumption is associated with a lower risk of heart failure irrespective of subtypes.
Abstract 14328: Performance of Current Cardiovascular Risk Scores Among the Brazilian Population: Findings From the ELSA-Brasil Study
Authors: Pedroso Aline , Barreto Sandhi Maria , Brant Luisa C , Ribeiro Antonio , Bittencourt Marcio S , Figueiredo Roberta , Khera Rohan
Published: December 2023

Background:
Cardiovascular disease (CVD) poses a significant health burden in low- and middle-income countries (LMIC), yet existing risk stratification strategies are primarily designed and validated in high-income countries.

Objectives:
We evaluated the discrimination and calibration of four CVD risk scores - Framingham General Risk (FGR), Pooled Cohort Equations (PCE), World Health Organization CVD score (WHO), and European Society of Cardiology (Score-2) - within the largest Brazilian community-based cohort study (ELSA-Brasil).

Methods:
We included all individuals aged 40 to 75 years in the prospective ELSA-Brasil without prior CVD who were followed for incident adjudicated CVD events (fatal and non-fatal MI and stroke or CHD death). We compared the mean predicted CVD risk scaled to 4 years with the observed 4-year CVD events across baseline risk groups (<5%, 5-10% and ≥10%.). For the total population and by race/sex group, we assessed discrimination by measuring the area under the ROC curve and calibration by predicted-to-observed risk (P/O) ratios using the Grønnesby-Borgan goodness-of-fit test.

Results:
12,742 individuals (52.9±8.1 years, 55.5% female) had 134 events. The model discrimination was acceptable for all scores (AUC>0.7), except for white women (AUC between 0.60 95% CI 0.44-0.76 and 0.64 95% CI 0.51-0.77). All risk scores overestimated the CVD risk in our study population (P/O ratio between 2.29 and 1.15). PCE and FGR scores displayed the highest overestimation (P/O ratio: 2.29 95% CI 2.07-2.51 and 2.19 95% CI 1.88-2.50, respectively), and the recalibrated WHO score for tropical Americas had the best calibration performance (P/O ratio: 1.15 95% CI 0.96-1.34).

Conclusion:
Current CVD risk scores have good discrimination but poor calibration in this admixed Brazilian population. The recalibrated WHO score showed the best calibration, highlighting the need for improved risk stratification and tailored risk-based prevention strategies in LMICs.
Abstract 14344: Pitfalls of ICD-10 Codes for Identifying Pulmonary Embolism in Electronic Records: Results From the Multicenter PE-EHR+ Study
Authors: Bikdeli Behnood , Bejjani Antoine , Khairani Candrika D , Lo Ying-Chih , Jimenez David , Barco Stefano , Mahajan Shiwani , Caraballo Cesar , Secemsky Eric A , Klok Erik , Hunsaker Andetta , Aghayev Ayaz , Muriel Alfonso , Hussain Mohamad A , Appah-Sampong Abena , MOJIBIAN HAMID , Lu Yuan , Lin Zhenqiu , Aneja Sanjay , Khera Rohan , Goldhaber Samuel , Zhou Li , Monreal Manuel , Piazza Gregory , Krumholz Harlan M
Published: December 2023

Background:
Many research studies from electronic databases and even the American Heart Association annual statistics for pulmonary embolism (PE) rely on the International Classification of Disease, 10
th
modification (ICD-10) codes. However, the validity of ICD-10 codes for PE remains uncertain.

Methods:
Using a pre-specified protocol, we identified three groups of patients in the Mass General-Brigham Health system hospitals (MGB, 2016-2021) in equal distribution: Those with ICD-10 Principal discharge codes for PE, those with ICD-10 secondary codes for PE, and those without codes for PE (N=578 each). The accuracy of ICD-10 codes for identification of PE was assessed in reference to review of each chart by two independent physicians who used pre-specified criteria for presence of PE. Weighted estimates were obtained by considering the total of number of hospitalizations at MGB in each group.

Results:
After excluding duplicates, 1712 entered the analysis (age: 60.6 years, 52.3% female). Using the ICD-10 PEs only in the Principal discharge diagnosis, sensitivity and specificity were 60.3% and 94.6%, respectively. Although use of Principal-or-secondary ICD-10 PE codes had a sensitivity of 99.8% in the study sample, the weighted sensitivity in the parent cohort was reduced to 83.2%. The positive predictive value of Principal ICD-10 discharge codes and Principal-or-secondary ICD-10 codes were 91.9% and 79.2%, respectively (Table).

Conclusions:
Although the Principal discharge diagnosis codes for PE have an excellent positive predictive value, they miss nearly 40% of new PE events in hospitalized patients. Integration of secondary discharge codes only partially improves the sensitivity at the cost of reducing the positive predictive value, highlighting the need for modified strategies, such as use combination with procedure codes, or use of natural language processing -when feasible -for identification of patients with PE.
Abstract 14362: The Columbia Score Predicts Incident Atrial Fibrillation and Flutter in Patients With Transthyretin Cardiac Amyloidosis
Authors: Chan Nicholas , Teruya Sergio , Mirabal Alfonsina , De Los Santos Jeffeny , Guadalupe Samantha , Rodriguez Carlos , Helmke Stephen , Cuomo Margaret , Smiley Dia , Biviano Angelo B , Dizon Jose , Wan Elaine Y , Yarmohammadi Hirad , Maurer mathew S
Published: December 2023

Introduction:
Atrial fibrillation/flutter (AF) is common in transthyretin cardiac amyloidosis (ATTR-CA). Given the high risk of systemic embolism, there is growing interest in the role of clinical scores for predicting new onset AF in affected patients to potentially guide early prevention of thromboembolic events. The CHARGE-AF scoring system was previously derived from the general population, but has not been validated in ATTR-CA. The Columbia staging system for ATTR-CA is prognostic for survival, but its utility in predicting incident AF is unknown. This study explored the incidence rate and risk scores for AF in ATTR-CA.

Methods:
This is a retrospective cohort study of 175 patients diagnosed with ATTR-CA who did not have any prior AF upon initial evaluation. We compared the baseline clinical characteristics of individuals with and without incident AF during subsequent follow-up. AF was ascertained based on review of electrocardiograms, continuous monitoring when available, device interrogations if applicable, and charted history. The Columbia score for amyloidosis staging was computed from: Gilmore stage + daily furosemide dose equivalents (0 points: 0 mg/kg, 1 point: between >0 to 0.5 mg/kg, 2 points: >0.5 to 1 mg/kg, 3 points: >1 mg/kg) + NYHA functional class. Time to event analysis was performed via Cox proportional hazard modeling to determine the factors associated with incident AF.

Results:
New onset AF developed in 41% (n=71) of ATTR-CA patients, with a median follow-up of 2.0 years for the overall population. Compared to those without incident AF, more patients with incident AF were males (93.0% vs 78.8%); self-identified as white race (78.9% vs 61.5%); and reported NYHA II-IV symptoms (91.5% vs 78.8%); but were less frequently of Hispanic ethnicity (2.8% vs 10.6%) or had a genetic variant (25.4% vs 49.0%), all p<0.05. On multivariable analysis, per point increase in Columbia score (HR 1.21, 95% CI 1.03-1.42, p=0.018) was associated with new onset AF, but gender, variant disease, CHARGE-AF, and left atrial volume index were not.

Conclusions:
About half of ATTR-CM patients developed incident AF during follow-up, which was predicted by the Columbia score, but not the CHARGE-AF score.
Abstract 14367: Multimodal Artificial Intelligence Algorithm to Distinguish Paroxysmal versus Persistent Atrial Fibrillation and Predict Outcomes After Ablation
Authors: Bernstein Hannah , Brooks Wesley , Sirish Padmini , Kreylos Oliver , Chiamvimonvat Nipavan , McCann Alexandra , Filkov Vladimir , Srivatsa Uma N
Published: December 2023

Introduction:
We aimed to develop effective multimodal machine learning (ML) techniques to predict: 1) duration of AF; 2) arrhythmia recurrence after ablation.

Methods:
Clinical data, intracardiac EGMs and metabolomic samples were obtained from patients undergoing AF ablation. Patients were prospectively followed to assess for recurrence after a 90-day blanking period with monitors every three months and if symptomatic. A prototype model was implemented via projection onto latent structures (PLS) logistic regression (LR), which accounts for collinearity in the predictors by estimating a small number of latent vectors that are aligned with the binomial response. PLS LR was used to estimate models for distinguishing paroxysmal from persistent AF and predicting recurrence. The latent structures identified by PLS LR combine strength from measurements of multiple correlated features. We generated a reference distribution to assess whether the model is better than chance by permuting the responses while keeping the inputs fixed. Models were compared based on the Akaike Information Criterion.

Results:
Three models were compared: EGM data (n=39), metabolomic data (n=29), multimodal approach on the combined two datasets (n=23). The multimodal model consistently produced a better fit despite smaller sample size. Only the model based on EGMs was significantly better than chance at distinguishing PAF from PeAF (p=0.03). The models based on EGMs and the combined data were significantly better than chance at predicting recurrence (p=0.02, p=0.04, respectively). Predictor EGM and metabolomics variables are shown in tables.

Conclusion:
Multimodal ML algorithm is promising to effectively combine multidimensional data for clinical use. The combined model consistently produced a better fit compared to the others, indicating that multimodal approaches are promising. According to AIC, the fit was better when the datasets were combined.
Abstract 14381: A Novel Non-Invasive Screening Device for Aortic Stenosis
Authors: Harb Serge C , Kassab Joseph , Collier Patrick H , Grimm Richard A , Ramchand Jay , Kapadia Samir R
Published: December 2023

Introduction:
Severe AS is a significant health concern in the elderly population, and a large proportion of asymptomatic cases are not receiving appropriate care. Early intervention is associated with a significant reduction in long-term mortality making early diagnosis and intervention crucial.

Hypothesis:
Recent progress in non-invasive (NI) hemodynamic measurements and AI has prompted the exploration of NI screening tools for AS. The ClearSight® system (Edwards) is a NI monitoring device using a finger cuff for continuous hemodynamic assessment. This study aims to evaluate its accuracy as a severe AS screening tool.

Methods:
7,000 consecutive patients referred for TTE were enrolled prospectively, between 12/2020 and 04/2022 and underwent concomitant non-invasive hemodynamic monitoring using the ClearSight
®
system. Complete data were obtained on 6,858 patients. The development cohort consisted of 5,334 patients, whereby an AI system was trained to interpret the data obtained from the device with the TTE data serving as the gold standard for diagnosis of severe AS. After the development phase, 1,036 patients were included in the validation cohort, whereby the trained AI system used the data obtained from the device to predict the presence of severe AS.

Results:
Severe AS was confirmed by TTE in 54 patients. Based on the optimal threshold (ROC curve), the sensitivity for detecting severe AS in patients without other VHD was 87%, with a NPV of 98.1%, and a specificity of 80%. When including all patients, with and without concomitant non-aortic VHD, the sensitivity remained at 87% for the same threshold, with a similarly very high NPV at 98.9%, while the specificity decreased to 70.7%.

Conclusions:
The ClearSight
®
system, a finger-cuff NI hemodynamic monitoring tool, serves as an excellent screening test for the early detection of severe AS, with high sensitivity and specificity, and a very high NPV in a large cohort of patients consecutively referred to a TTE laboratory.
Abstract 14389: Mitigating Health Disparities by Improving Access to Advanced Multidisciplinary Care for Vulnerable Patients With Intermediate and High-Risk Pulmonary Embolism
Authors: Alviar Carlos L , Zhang Robert , Padilla-Lopez Mireia , Postelnicu Radu , Elbaum Lindsay , Wan Kah-Loon , Greco Allison , Alam Usman , Hena Kerry , Mukherjee Vikramjit , Tarabanis Constantine , Harari Rafael , Hall Sylvie , Keller Norma , Bangalore Sripal
Published: December 2023

Background:
Vulnerable patients, including minorities and underserved populations whose care rely on public hospitals, have limited access to advanced pulmonary embolism (PE) treatment, particularly when catheter-based therapies (CBT) and escalation of care are needed. Our aim is to describe the multidisciplinary pulmonary embolism response team (PERT) program for the largest public health system in the country, as a strategy to mitigate healthcare disparities and improve access to care.

Methods:
We collected clinical, demographic and socioeconomic data from patients with intermediate-high and high-risk PE undergoing CBT at Bellevue Hospital, a PERT referral center and level 1 shock center for New York City’s Health and Hospitals’ network. Outcomes included in-hospital mortality and complications from CBT.

Results:
Sixty-one patients were included (42.6% women, age 57 ± 13.7 years) between October, 2022 to April 2023; 80.3% had intermediate-risk PE, 19.7%% had high-risk PE. The majority were black (57.4%), followed by Hispanic (13%). A total of 13% were uninsured, 9.8% were undocumented and 50.8% lived below the poverty level for New York City. The level of education was 8th grade or less in 4.9% of patients, high school in 29.5%, at least 2 years of college in 6.6%, >4 years of college in 8.2%, master’s degree in 4.9% and unknown in 46%. Disease severity markers (CPES, PESI, BOVA, lactate, troponin and BNP) did not vary by ethnic group. There were no differences in mortality between white and non-white patients (figure); 3(4.9%) patients required rescue extracorporeal support and there were no procedural related complications.

Conclusions:
Our multidisciplinary PERT program demonstrates feasibility to provide care to underserved and vulnerable populations with excellent outcomes, serving as a strategy to help decrease healthcare disparities, particularly for advanced therapies for a challenging condition such as intermediate and high-risk PE.
Abstract 14391: Biomarkers, Proteomics, and Echocardiography Lend Insights into Cardiovascular Death in HFrEF: A VICTORIA Substudy
Authors: Shah Palak , Zheng Yinggan , Pieske Burkert , Melenovsky Vojtech , Lam Carolyn S , Sliwa Karen S , Butler Javed , Ezekowitz Justin A , deFilippi Christopher , OConnor Christopher , Roessig Lothar , Tromp Jasper , Westerhout Cynthia M , Voors Adriaan A , Armstrong Paul W
Published: December 2023

Background:
Using data from the VICTORIA ECHO substudy in high-risk patients with heart failure with reduced ejection fraction (HFrEF), we evaluated the potential complementary role of cardiac function, biomarkers, and proteomics in association with cardiovascular death (CVD), a key component of the primary composite (HF hospitalization or CVD).

Hypothesis:
Measurement of cardiac biomarkers, proteins, and ECHO parameters may provide insights into the mechanism of CVD in HFrEF.

Methods:
At baseline, left ventricular ejection fraction (LVEF) and LV end-systolic volume index (LVESVI) on ECHO, 6 quantitative biomarkers, and 92 proteins (Olink CVD III panel) were assessed by blinded core labs. Adjusted (MAGGIC) associations and HRs (95% CIs) are presented. Proteomics associations were adjusted for false discovery rate.

Results:
Of 583 patients, 96 (16.5%) had CVD (21.6/100 pt-years) a median 8 months (IQR 6-11) from randomization. See Table for MAGGIC-adjusted HRs for LVEF, LVESVI, and biomarkers. NT-proBNP was most strongly associated with CVD (HR per doubling 1.53 [1.32-1.77]). Proteins significantly associated with CVD were cathepsin D (2.32 [1.62-3.32]), matrix metalloproteinase-2 (2.31 [1.45-3.68]), IL-2 receptor (1.74 [1.40-2.14]), transferrin receptor (1.64 [1.31-2.04]) and tumor necrosis superfamily (1.88 [1.41-2.50]) (Fig).

Conclusions:
After MAGGIC adjustment, a rise in LVESVI, but not LVEF, was associated with CVD. Upregulation of selected biomarkers/proteins related to myocardial wall stress, extracellular matrix turnover, inflammation, and oxidative stress were also associated with CVD and may serve as novel future therapeutic targets in HFrEF.
Abstract 14399: Development of Heart Failure in High-Risk Post-Myocardial Infarction Patients: An Analysis of the Paradise-MI Trial
Authors: VanDer Meer Peter , Braunwald Eugene , Pfeffer Marc A , Granger Christopher , Kober Lars , Lewis Eldrin F , Maggioni Aldo Pietro P , Mann Douglas L , McMurray John J , Rouleau Jean L , Solomon Scott , Steg Philippe G , Jering Karola , Berry Gerald A , Fernandez Alberto , Claggett Brian
Published: December 2023

Objectives:
The aims of this study were i) to examine the incidence, risk factors and subsequent mortality after high-risk acute myocardial infarction (AMI) and ii) compare the effects of sacubitril/valsartan with the ACE inhibitor ramipril across heart failure (HF) risk categories.

Background:
The contemporary risk of developing HF following AMI in the coronary reperfusion era is not well documented.

Methods:
We analyzed the 5661 patients enrolled in the PARADISE-MI trial which compared sacubitril-valsartan to ramipril after AMI. Patients were required to have acute pulmonary congestion and/or left ventricular systolic dysfunction at the time of AMI, but no history of HF. We analyzed a composite outcome of first occurrence of investigator-reported HF hospitalization or outpatient development of HF.

Results:
During a median follow up of 22 months, 734 patients (13%) developed a first episode of HF, of which 496 (68%) were a hospitalization and 238 (32%) an outpatient HF episode. Only 74 patients (10%) experienced another AMI prior to developing HF. Independent predictors for the development of HF were a lower baseline left ventricular ejection fraction (LVEF), pulmonary congestion, diabetes, older age, higher heart rate, previous MI, and renal dysfunction. A risk-score showed an exponential increased risk of developing HF with a higher score (Figure 1). The relative effect of sacubitril/valsartan compared to ramipril was similar across the HF risk spectrum (p-value for interaction=0.14). The hazard ratio for cardiovascular mortality after outpatient

development of HF (in comparison to no event) was 3.9 (95% CI 2.5-6.2) and after an HF hospitalization was 10.0 (95% CI 7.8-12.8).

Conclusion:
New onset HF after high-risk AMI was common and resulted in a 10-fold higher cardiovascular mortality than no HF. Sacubitril/valsartan, compared to ramipril, showed similar efficacy across the HF risk spectrum.
Abstract 14414: Association of Genetically Predicted Biomarkers of Iron Homeostasis and Cardiomyopathy Risk: A Two-Sample Mendelian Randomization Study
Authors: Huang Hao , Wei Hua
Published: December 2023

Background:
Observational studies produced inconsistent results of the association between iron status and cardiovascular diseases. Previous Mendelian randomization (MR) study prompted a protective effect of iron status in coronary heart disease.

Aims:
Using genetic instrumental variables, we evaluated how the risk of non-ischemic cardiomyopathy and its different phenotypes are affected by genetically predicted systemic iron status.

Methods:
Two-sample MR analyses were performed to estimate the causal effect of four biomarkers of systemic iron status on diagnosed cardiomyopathy and its subtypes in 242,607 participants from the FinnGen research project. Inverse-weighted method and multiple sensitivity analysis were conducted to confirm the results.

Results:
The level of transferrin saturation was significantly associated with an increased risk of cardiomyopathy (OR per SD, 1.17; 95% CI, 1.13-1.38) when using nine separately selected genetic instruments. Conservative estimates were obtained by pooling results across four mutual genetic variants (rs1800562, rs1799945, rs855791 and rs57659670). Accordingly, genetically determined serum iron (OR, 1.25; 95% CI, 1.13-1.38), ferritin (OR, 1.49; 95% CI, 1.02-2.18) and transferrin saturation (OR, 1.21; 95% CI, 1.04-1.39) were positively associated with cardiomyopathy risk, while total iron binding capacity, a marker of reduced iron status, was protective (OR, 0.80; 95% CI, 0.65-0.98). The risk effect of iron status was more evident in hypertrophic cardiomyopathy and related heart failure. Red blood cell traits, blood pressure and blood lipids were not mediated in the causal effect. Results were robust in all sensitivity analyses.

Conclusions:
These analyses support a causal effect of increased systemic iron status on higher risk of non-ischemic cardiomyopathy. Modulation of iron status may, therefore, directly influence cardiomyopathy risk.
Abstract 14448: Graft Loss and Rejection Following COVID in Pediatric Heart Transplantation - A Pediatric Heart Transplant Society (PHTS) Propensity Matched Analysis
Authors: Spinner Joseph , Conway Jennifer , bocchini claire , Cantor Ryan S , Koehl Devin , Kirklin James K , Wright Lydia , Molina Kimberly , Shaw Fawwaz , Villa Chet , West Shawn C
Published: December 2023

Introduction:
While short-term outcomes following COVID among pediatric heart transplant (HT) recipients have been described, graft outcomes including the risks of subsequent graft loss and rejection following COVID are unknown.

Hypothesis:
We sought to determine the overall trends of post-HT survival during the COVID pandemic and determine if there was an increased risk for subsequent graft loss and/or rejection following post-HT COVID.

Methods:
All pediatric recipients of first HT between 1/2003-6/2022 in the Pediatric Heart Transplant Society
(
PHTS) database were included. To assess if early post-HT survival changed during the COVID pandemic, 2-year HT survival was compared among those who underwent HT in 2014-2016, 2017-2019, and 2020-2022. To compare the risks of graft loss and rejection (acute cellular and/or antibody-mediated) between those with vs without post-HT COVID, a 1:2 (COVID vs non-COVID) propensity-score matched analysis using multiple pre-HT and post-HT factors (including exact matches for HT year and time post-HT) and Kaplan Meir analysis were performed. Patients with COVID within 3 months post-HT were excluded.

Results:
The 2-year post-HT survival was similar among patients who underwent HT across the 3 eras (Fig 1A). Among the overall 6634 patients (n = 888 [13%] with post-HT COVID), 861 patients with post-HT COVID and 1716 without post-HT COVID were included in propensity-score matching. There was no difference in the risk of subsequent graft loss (Fig 1B) or rejection (Fig 1C) among those with vs those without post-HT COVID.

Conclusions:
No differences were observed in early pediatric post-HT survival during the COVID pandemic compared to the immediately prior era. Post-HT COVID did not increase the risks of subsequent graft loss or rejection. Longer-term follow up is necessary to look at other potential post-HT COVID outcomes, such as coronary allograft vasculopathy.
Abstract 14470: Right Ventricular Flow Visualization and Characterization via High Speed Volumetric Echo-PIV
Authors: Farsiani Yasaman , Falahatpisheh Ahmad , Brown Tawnya , Caudill Antonina , Jackman Susan , Matusov Yuri , Pedrizzetti Gianni , Singh Siddharth , Kheradvar Arash
Published: December 2023

Introduction:
Although 4D echocardiography is used for many clinical applications, the evolving vortex flow in the right ventricle (RV) is relatively unknown and cannot be characterized with conventional echocardiography. An obstacle is that acquiring high frame rate (>100fps) data in presence of contrast is challenging and has not yet reported.

Hypothesis:
High frame-rate 4D echocardiographic data in presence of contrast can elucidate RV vortex flow via volumetric Echo-PIV (V-Echo-PIV).

Methods:
We devised a new transthoracic echocardiography (TTE) protocol using a Philips EPIQ CV9 ultrasound system with a 3D matrix probe (X5-1c) to acquire high frame-rate 4D data for processing with V-Echo-PIV. Apical RV focused view was used for full-volume acquisition by limiting the sector width and imaging depth solely to the entire RV. Visualization of the RV flow and wall dynamics was achieved by IV administration of Optison™ and Normal Saline. VolDICOMs were processed with V-Echo-PIV to obtain RV blood flow velocity field during the full cardiac cycle.

Results:
We improve the frame rates' scan lines to +30Hz. A 100Hz is achieved by stitching 4 cycles. We show that 4D RV flow can be quantified and characterized at high temporal resolution using V-Echo-PIV. Fig. 1A shows cine blood velocity in a healthy subject with a 51bpm heart rate. For which, V-Echo-PIV acquired 117 three-dimensional vector fields in one cardiac cycle, given the setting of 100Hz acquisition rate. The figure features flow patterns from systole to diastole, from left to right. Fig. 1B depicts the iso-surface of transient tricuspid vortex during diastolic RV filling.

Conclusions:
Enabled by high speed acquition in presence of contrast, V-Echo-PIV can be used as a viable alternative to 4D Flow MRI to visualize and evaluate real-time intra-cardiac blood flow, as it requires only a very short acquisition time and can be used wherever an echocardiography machine with matrix probes is available.
Abstract 14479: Compound Heterozygosity With Two Novel Mutations in MYBPC3 as a Cause of Severe and Early-Onset Hypertrophic Cardiomyopathy
Authors: Sanchez-Moreno Jose. M , CARRERAS BLESA CARMEN , Rodriguez Vazquez del Rey Maria del Mar , Jimenez-Jaimez Juan , Macias Ruiz Rosa , Bermudez-Jimenez Francisco J , Garcia Roa Maria Dolores , Diaz Rueda Laura , Cardenas Ivonne J , Perin Francesca
Published: December 2023

Case presentation:
A 8-year-old male was diagnosed with severe hypertrophic cardiomyopathy (HCM) after a cardiac arrest from which he was successfully defibrillated. Maximal wall thickness was 23 mm (z-score 6.36) on echocardiography. An implantable cardioverter defibrillator (ICD) was implanted and atenolol was started. After 4 ventricular fibrillation-terminating ICD shocks in the following 2 months, further treatment is under consideration. A genetic test identified the likely pathogenic intronic variant (c.1927+337G>T) in the MYBPC3 gene. An additional variant in the same gene (p.Arg817Gly), of uncertain significance but potentially relevant for the phenotype, was also found. His 10-year-old sister was also diagnosed with severe HCM, genetic test identified the two previously referred variants and ICD was also implanted. In the 4-year-old one sister, who is apparently healthy, only the likely pathogenic intronic variant (c.1927+337G>T) was found. Regarding their parents, both with no evidence of cardiomyopathy, c.1927+337G>T variant was identified in the father, while p.Arg817Gly was present in the mother.

Discussion:
This clinical case is noteworthy as an example of compound heterozygosity in which each parent donates one alternate allele, being these alleles located at different loci within the same gen, which emphasizes the importance of family genetic testing. The variant of uncertain significance p.Arg817Gly appears to be a disease modifier, causing the phenotype to be expressed early and severely in the presence of the probably pathogenic intronic variant c.1927+337G>T in MYBPC3. This deep intronic variant has not been described previously but was found in thirteen index cases referred for HCM and a history of familial sudden death at an early age, being overrepresented in the cohort of HCM in the north of Spain. Being a carrier of both these two novel variants appears to cause an extremely aggressive childhood-onset phenotype.
Abstract 14481: Engineered Cardiac-Specific AAV Capsids From a Novel Next-Generation Platform (next-CAP) With Cross-Species Selection for Cardiac-Targeted Gene Therapy
Authors: Schweiggert Jörg , Habeck Gregor , Hinkel Rabea , Kehr Dorothea , Cimen Kristin , Kramp Xenia , Lerchenmueller Marc , Katus Hugo , Most Patrick , Busch Martin
Published: December 2023

Background:
Adeno-associated virus (AAV) based gene therapy bears the potential to transform future clinical care of hereditary and acquired heart failure. However, the broadly used AAV9 serotype exhibits fatal liver toxicity in clinical studies and requires long-term immunosuppressive therapy when used systemically e.g., for LAMP2 gene-associated cardiomyopathy.

Hypothesis:
AAVs with genetically-engineered cardiac tropism are key for safe and efficient delivery of therapeutic gene replacement, silencing or editing systems to the diseased heart with minimized off-target organ transduction after a simple systemic administration.

Technology & Results:
We developed novel cardiac-specific AAV capsids by a next-generation experimental-bioinformatic AAV capsid development platform (next-CAP) employing mouse, farm pig and non-human primate models. A highly diverse capsid library with more than 100 million variants was generated from novel mammalian heart AAV isolates integrating DNA shuffling and peptide display approaches and underwent a two-step cross-species
in vivo
evolution. Implementing a unique molecular identifier strategy eventually allowed for combined long- and short-term sequencing to capture 77 novel AAV capsid variants displaying highest enrichment in hearts over all other organs, including the liver with superior patterns to AAV9. Subgroups of the top heart-AAV capsid portfolio displayed an overall sequence homology of up to 99.5% identity highlighting the presence of novel cross-species conserved heart-homing motifs. As producibility was another inherent screening criteria, our cardiac-specific AAV capsid portfolio already provides scalable manufacturing characteristics for in vivo indications.

Conclusion:
Our proprietary portfolio of novel heart-specific AAV capsids now enables the systematic development of optimal therapeutic capsid-promoter-transgene ensembles for further dose-expression, -efficacy and -toxicity assessments for various hereditary and acquired HF indications in suitable model systems. In summary, we developed an efficient and versatile platform for the generation of next-generation AAV capsids for heart-specific gene therapy of yet uncurable rare and common cardiac diseases.
Abstract 14485: LDHA-Lactate Promotes Smooth Muscle Remodeling and Pulmonary Hypertension Through Lactylation of TOP1 and EMILIN1
Authors: Jiang Lifeng , Zhyvylo Iryna , Goncharov Dmitry , Teos Leyla , Lin Derek , Franzi Lisa , Saiyed Aisha , Neeli Sanjana , Kenyon Nicholas , Wolters Paul , Delisser Horace , Kudryashova Tatiana , Goncharova Elena
Published: December 2023

Background:
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of small pulmonary arteries (PA) due to hyper-proliferation of resident PA cells, leading to elevated right ventricular (RV) afterload and heart failure. PA smooth muscle (SM) cells (PASMC) in PAH have metabolic shift to glycolysis and lactate over-production.

Goals:
To investigate the role of lactate over-production in PA remodeling and PAH.

Methods:
RT-PCR, immunohistochemical, immunoblot, proteomic analyses; proliferation (Ki67), lactate, apoptosis assays; SU5416/Hypoxia (SuHx) rat and mouse models of PH.

Results:
Lactate dehydrogenase A (LDHA) was over-expressed in SMα-actin-positive areas of small muscular PAs from PAH subjects and rodents with SuHx PH, and distal human PAH PASMC compared to controls, promoting lactate over-production, consequent up-regulation of Yap/Taz, Akt-mTOR, increased proliferation and survival.
SM22α-Ldha-/-
mice were protected from SuHx-induced PH and RV hypertrophy. Lysine lactylation (Kla) was increased in small PAs and PASMC from human PAH lungs. Proteomic analysis identified 12 non-histone proteins that were hyper-lactylated in PAH PASMC. Following validation revealed that hyper-lactylation induced over-accumulation of TOP1 and deficiency of EMILIN1 in small PAs and PASMC from PAH lungs, leading to up-regulation of Yap/Taz, Akt-mTOR, TGFβ1, and increased proliferation. Lactate self-supported its over-production by up-regulating glycolysis and LDHA overexpression through EMILIN1-TGFβ1-HIF1α loop. Human PAH PASMC had elevated lactate secretion; exogenous lactate induced proliferation of control PAEC and PAAF. Pharmacological inhibition of LDHA-lactate reduced proliferation and selectively promoted apoptosis in human PAH PASMC, reversed SuHx-induced PA remodeling, PH, and RV hypertrophy in mice.

Conclusions:
LDHA-driven lactate over-production promotes proliferative, apoptosis-resistant PASMC phenotype, pulmonary vascular remodeling, and PH via hyper-lactylation and over-accumulation of TOP1, deficiency of EMILIN1, and consequent activation of Yap/Taz, Akt/mTOR, and TGFβ1. Targeting LDHA-lactate network could represent potentially attractive strategy to treat PAH.
Abstract 14488: Male Predominant Cardiac Phenotype in Cardiac-Specific Gpd1-l Knockout Mice
Authors: Mehdi Haider , Greiner Alexander , Dierdorff Jason , Yoon Jin-Young , Current Kyle , Kutschke William J , Colgan Diana , London Barry
Published: December 2023

Introduction:
We reported that a mutation in Glycerol-3-Phosphdate Dehydrogenase-1 Like (GPD1L-A280V) is linked to Brugada Syndrome (BrS). This mutation increases acetylation and reduces surface expression of Nav1.5, and reduces inward Na+ current (INa) in HEK293 cells and rat neonatal cardiac myocytes. Global homozygous knockout of Gpd1-l in mice (Gpd1l-/-) was usually lethal, though we noted increased Nav1.5 acetylation, decreased INa, and pharmacologically inducible arrhythmias in Gpd1l+/- heterozygotes. Cardiac-specific deletion of Gpd1l (cGpd1l-/-) led to ventricular arrhythmias, contractile dysfunction, and a BrS-like ECG phenotype in males. Here, we extend our study to female cGpd1l-/- mice.

Methods:
cGpd1l
-/-
mice were generated by crossing floxed (Gpd1l
fl/fl
) mice with αMHC-Cre expressing mice. ECGs and echocardiograms (echos) were recorded at 6 and 9 months of age in cGpd1l
-/-
mice and Gpd1l
fl/fl
littermate controls.

Results:
At 9 months of age, male cGpd1l-/- mice compared to Gpd1lfl/fl controls had increased end diastolic and end systolic volumes (EDV, 108±67 vs 27±3 μL, p=0.02; ESV; 80±66 vs 6±2 μL; p=0.03), and markedly reduced ejection fractions (EF, 33±18% vs. 77±7%, p=0.001). Female cGpd1l-/- mice, on the other hand, had no changes to EDV, ESV, or EF (Figure A). The echo changes in male mice were minimal at 6 months. ECG recordings of ~9-month-old cGpd1l-/- male mice compared to Gpd1lfl/fl controls showed prolonged PR interval (52±1.1 vs. 40±2.7 ms; p=0.05) and QRS duration (17.8±1.5 vs. 15.2±1.1 ms; p=0.01) with no change in heart rate (Figure B). ECG parameters were also unchanged in cGpd1l-/- female mice.

Conclusions:
Cardiac-specific disruption of Gpd1l causes ventricular dysfunction, conduction abnormalities and arrhythmias in male but not female mice. Further investigation into the mechanisms underlying the sex-dependent phenotype of Gpd1l-/-mice and whether this impacts the male predominance of BrS in humans is warranted.
Abstract 14509: Life’s Simple 7 Predicts Mild Cognitive Impairment and Dementia in an Older Adult Population
Authors: Lopez Kyra E , Katz Benjamin , Davy Brenda M , Davy Kevin P
Published: December 2023

Introduction:
The American Heart Association’s Life’s Simple 7 (LS7) is a metric used widely in cardiovascular disease research. Lower scores on Life's Simple 7 predicts a lower performance on measures of cognitive functioning in young and middle-aged adults. Whether this is the case in older adults, however, is unclear.

Hypothesis:
Higher LS7 scores at baseline will be associated with a reduced risk of mild cognitive impairment (MCI) or dementia in older adults.

Methods:
Data from the Health and Retirement Study (HRS) between 2010 to 2018 was used in the analysis. The respondents were older than 50 years old and free from dementia and MCI at baseline. A survival-analysis was used and failures were defined as having MCI or dementia as determined by a 27-point Telephone Interview for Cognitive Status (TICS). LS7 scores were computed using smoking status (current and former), physical activity, diet, blood pressure, total cholesterol, blood glucose, and body mass index (BMI). A cox proportional hazard model was used to evaluate hazard ratio of developing mild cognitive impairment (MCI) and dementia in older adults.

Results:
There were 1,604 respondents with complete data included in this analysis. Of these respondents, 563 (35.1%) were male and 1,041 (64.9%) were female. 1,224 (76.3%) were white, 236 (14.7%) were black, and 143 (8.9%) were of another race. The average age of the respondents at baseline was 62.3±10.6 years. In 7,505 person-years, there were 1,197 events of MCI or dementia. After adjusting for age, gender, and educational attainment, a LS7 score less than 5 was associated with a 1.51 times higher risk of MCI or dementia than a LS7 score greater than 8 (p < 0.005). However, LS7 scores between 7 or 8 was not significantly associated with increased risk of MCI or dementia compared to a LS7 score greater than 8 (HR: 1.12, p = 0.09).

Conclusions:
Lower LS7 score is associated with significantly lower performance on a measure of global cognitive functioning. As in young and middle-aged adults, maintaining a heart-healthy lifestyle may be important in preventing cognitive decline in older adults.
Abstract 14518: Interactive Effects of Statins, Obesity, and Cardiorespiratory Fitness in Type 2 Diabetes Mellitus Incidence
Authors: Kokkinos Peter F , faselis charles J , Myers Jonathan , Samuel Immanuel B , LAVIE Carl J , Gollie Jared , Lamonte Michael J , Pittaras Andreas , Sen Sabyasachi , Nylen Eric
Published: December 2023

Introduction:
Statin therapy and obesity are associated with increased risk of developing type 2 diabetes mellitus (T2DM). Conversely, cardiorespiratory fitness (CRF) is inversely related to T2DM incidence. The interaction between statin therapy, obesity, and CRF has not been addressed.

Hypothesis:
Obesity and statins will be associated with increased risk of T2DM, while CRF will mitigate this increased risk.

Methods:
From the ETHOS cohort, we identified 570, 054 patients (age 60.7±10.1 years) with no T2DM. All completed a standardized exercise treadmill test (ETT) with no evidence of ischemia. Subsequently, 322,805 (56.6%) were treated with statins for at least 8 months (mean 9.5±5.9 years) and 247,249 were not. Participants were classified based on body mass index (BMI) as normal weight (BMI<25.0 kg/m
2
), overweight (BMI 25.0-29.9 kg/m
2
), Obese-I (BMI 30.0-34.9 kg/m2), and Obese-II (BMI ≥35.0 kg/m
2
). We established five CRF categories based on age-specific quintiles of peak metabolic equivalents achieved: Least-Fit (n=95,071); Low-Fit (n=133,404); Moderate-Fit (n=110,973); Fit (n=158,004) and High-Fit (n=72,602). Adjusted Cox proportional hazards models were constructed to evaluate the association between BMI, statin therapy and T2DM risk, and the interaction with CRF status.

Results:
During the follow-up period (median 10.3 years), 44,662 developed T2DM (7.4 events/1,000 person-years of observation). The risk of developing T2DM was 44% higher in those treated with statins [Hazard Ratio (HR) 1.44; 95% confidence interval (CI) 1.41-1.48)] compared to those not on statin therapy. The risk increased progressively with higher BMI levels and was nearly 3 times higher for those in the Obese-II category (HR 2.96, CI 2.85-3.06). When T2DM risk was assessed across CRF categories within BMI groups, we noted a progressive decline in T2DM risk with increased CRF regardless of statin therapy or BMI status. The adjusted risk was approximately 25% to 40% lower for those in the two highest CRF categories.

Conclusions:
Statin therapy and obesity were associated with increased risk of developing T2DM. This risk was mitigated significantly with increased CRF regardless of BMI status.