bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4146438: IgA-Deficiency Attenuates Angiotensin II-Induced Hypertension in Mice
Authors: Monga Jasmeen Kaur , Zhou Annie , Wang Tao , Momen Abdul , Siraj M. Ahsan , Husain Mansoor
Published: November 2024

Background:
Hypertension [HTN] has been associated with B cell-derived immunoglobulins, particularly IgA. In spontaneously hypertensive rat and humans, IgA has been implicated in HTN pathophysiology, but the mechanisms are not known. Here we explore effects of angiotensin-II [Ang-II]-induced HTN in IgA knockout [
-/-
] mice.

Methods&Results:
Invasive hemodynamic assessments during anesthesia showed male 10-12 wk old IgA
-/-
mice to have lower baseline systolic blood pressure [SBP] vs.
non
-littermate IgA
+/+
controls housed separately (86.8±2.1 vs. 104.0±2.7 mmHg; N=18-19/group; p<0.0001). Metabolic studies revealed increased 24-h urine (0.082±0.003 vs. 0.055±0.003 mL/g body weight; N=22-23/group; p<0.0001) and Na
+
(0.24±0.02 vs. 0.17±0.02 mg/d/g; N=11-12/group; p<0.05) excretion as compared to
non
-littermate IgA
+/+
controls. Next, male 10-12 wk old IgA
-/-
and IgA
+/+
littermate
controls received Ang-II (500 ng/kg/min) via osmotic minipumps for 28d. Surprisingly, IgA
-/-
and
littermate
IgA
+/+
controls showed no differences in SBP in response to Ang-II (150±18 vs. 135±22 mmHg; N=5/group; p=0.75). As mice engage in coprophagy, allowing passive IgA transfer between co-housed littermates, we separately crossed IgA
-/-
and IgA
+/+
females with IgA
-/-
and IgA
+/+
males to yield separately housed IgA
-/-
and IgA
+/+
offspring. In this setting, IgA
-/-
offspring showed blunted SBP response to Ang-II vs. IgA
+/+
offspring (103±18 vs. 152±14 mmHg; N=5/group; p<0.0001), demonstrating how passive IgA transfer via breastmilk or coprophagy permits Ang-II-induced HTN. Finally, we crossed IgA
-/-
females with heterozygous IgA
+/-
males and separated offspring by genotype at weaning. In this experiment as well, IgA
-/-
mice showed an attenuated SBP response to Ang-II
vs
. co-housed (until weaning) IgA
+/+
littermates
(106±22 vs. 137±27 mmHg; N=6-9/group; p<0.05), indicating that IgA
+/+
mice become hypertensive despite not receiving IgA from breast milk.

Conclusion:
IgA
-/-
mice exhibit reduced baseline SBP and increased 24-h Na
+
and water excretion as compared to separately housed IgA
+/+
controls. Co-housing influences SBP responses in mice, likely due to passive IgA transfer. Separating animals by genotype at weaning confirmed loss of the SBP response to Ang-II in IgA
-/-
mice, highlighting the importance of IgA in Ang-II-induced HTN. Further studies are underway to understand if this effect is mediated by changes in mucosal immunity and microbiome.
Abstract 4146444: Higher total physical activity levels are associated with decreased all-cause mortality in patients with Chagas disease
Authors: Mediano Mauro , Ribeiro Leonardo , Diferenz Erica , Mazzoli-Rocha Flavia , Rodrigues Junior Luiz Fernando , Goncalves Tatiana , Paravidino Vitor , Kasal Daniel , Saraiva Roberto , Hasslocher-Moreno Alejandro , Mendes Fernanda
Published: November 2024

Introduction:
Higher levels of physical activity (PA) are associated with lower mortality in different populations. However, no previous study evaluated this association among patients with Chagas disease (CD), a neglected tropical disease that affects approximately 7 million people worldwide associated with high mortality rates in its more advanced stages.

Aim:
This study aimed to assess the association between PA level and all-cause mortality in patients with CD.

Methods:
This was an observational study including CD patients (confirmed by two serological methods) followed-up at the National Institute of Infectious Diseases Evandro Chagas (INI/Fiocruz). Baseline assessment was conducted from March 2014 to March 2017. PA level was assessed using International Physical Activity Questionnaire short version (IPAQ). Deaths were assessed using patients' medical records and the regional death registry system. The association between PA levels (tertiles and as continuous variable) and mortality was determined by log-rank test and Cox regression models. Adjusted analyses were conducted for potential confounding variables including age, sex, hypertension, diabetes mellitus, dyslipidemia, obesity, clinical form of CD, ejection fraction, and prior use of benznidazole.

Results:
Of the 361 participants included, 56.2% were women (mean age 60.7±10.7 years). During a median follow-up of 7.2 years (IQR 25-75% 5.4 to 8.0 years), there were 90 deaths (24.9%), of those 39 (32.2%) in the lowest PA tertile, 32 (26.7%) in the intermediate PA tertile, and 19 (15.8%) in the highest PA tertile (p=0.006, Log-Rank test). In adjusted Cox regression analysis, the risk of death was lower in the highest PA tertile compared to those in the lowest PA tertile (HR 0.55; 95% CI 0.31 to 0.96; p<0.001; Table). Furthermore, each increase of 100 MET.minutes/week was associated with a 2% lower risk of all-cause mortality. Similar results were observed after excluding deaths within the first 2 years.

Conclusion:
A linear dose-response association was observed between increased levels of PA and reduced mortality, demonstrating the importance of encouraging PA in this population.
Abstract 4146472: 30-day and one-year outcomes of patients with severe aortic stenosis after TAVI using Myval : A Meta-analysis
Authors: Hasabo Elfatih , Abo Ali Amira , Hemmeda Lina , Salah Alaa , Alrawa Salma S. , Elgadi Ammar , Abdalmotalib Malaz M. , Eissa Abdullatif Yasir H , Mahmmoud Fadel Allah Mohammed , Sultan Sherif , SOLIMAN OSAMA
Published: November 2024

Introduction:
Transcatheter aortic valve implantation (TAVI) has been growing rapidly. The Myval balloon-expandable (BE) valve is a novel valve used for treating patients with severe aortic stenosis. No previous meta-analysis has assessed the different outcomes of TAVR using the Myval. We aim to evaluate the performance and outcomes of the Myval BE valve in patients with aortic stenosis.

Methodology:
A systematic search was done in PubMed, Scopus, Web of Science, Embase, and Cochrane from inception to June 2024. We used the relevant keywords to include studies that reported the outcomes of people who underwent a Myval balloon-expandable procedure for Aortic stenosis. 30-day and one-year outcomes were extracted across the studies. Device success of Myval was identified using Valve Academic Research Consortium (VARC)-2 and VARC-3 criteria.

Results:
Thirteen studies comprising 1256 patients of aortic valve stenosis were included. Of those, 679/1198 (56.7%) were males. The device success of Myval reached 97% CI [0.95, 0.98] across in included studies (Figure 1). Following TAVI, the procedural death and life-threatening bleeding with Myval were 1.3%, CI [0.6, 2.8], and 0.6%, CI [0.2, 2.5], respectively. Stroke cases following Myval were noticed in 3.6%, CI [2.2, 5.6] of total participants.

After following for 30-days, all-cause mortality and moderate or severe aortic regurgitation cases were 1.8%, CI [1.0, 3.2], and 2.3%, CI [1.0, 5.0], respectively. Also, the transvalvular mean pressure gradient was found to be 7.7 mmHg, CI [7.5, 8.0]. One year follow-up showed that all-cause mortality slightly increased, reaching 8.4% CI [6.1, 11.4] and stroke cases were noticed in 5.2%, CI [3.4, 7.9]

Conclusion:
Myval showed good safety and efficacy outcomes after 30 days and one-year following the TAVI.
Abstract 4146533: Association of Quantitative Echocardiographic Parameters with Peak VO2, Heart Rate Recovery, and VE/VCO2 from Cardiopulmonary Exercise Testing
Authors: Sharma Arundhati , Sharma Anubhuti , Chaliki Kalyan , Viggiano Taylor , Chaliki Hari , Reddy Satyajit
Published: November 2024

Background:
Cardiopulmonary Exercise Testing (CPET) analyzes physiologic information with gas exchange during exercise. Peak oxygen volume consumption (absolute peak VO2 and percent predicted peak VO2), minute ventilation divided by carbon dioxide volume (VE/VCO2 slope) and heart rate reduction after 1 minute of recovery (heart rate recovery, HRR) all have well-established prognostic cardiovascular implications.

Aim:
Given the wider use of echocardiography, we aimed to see if important CPET data could be determined from resting transthoracic echocardiography (TTE).

Methods:
In this retrospective study, cardiology patients above 18 years who underwent both resting TTE and a max-effort CPET within 3 months of each other (2017-2022) were included. Patients with a history of coronary artery bypass grafting, valve surgery, pacemakers, congenital heart disease, severe valve dysfunction and pulmonary hypertension were excluded before analysis. Univariate analysis with Spearman correlations was used to assess the relationship between 4 CPET measurements {absolute peak VO2 per kg, percent predicted peak VO2/kg (adjusted for age, sex and body surface area), HRR, and VE/VCO2}; and 22 quantitative TTE parameters. Bonferroni correction was applied within each set of correlations, with significance set at p-values <0.025. Multivariate linear regression models were built for all the related TTE measurements to assess relationship with the 4 CPET parameters, adjusting for age and sex.

Results:
Table 1 shows, out of 1909 patients analyzed, our regression model is strongest for absolute peak VO2/kg (R-squared=0.57), with 3 significantly associated TTE parameters. For percent-predicted peak VO2 per kg, 4 TTE variables were significantly associated. For heart rate recovery, only LV stroke-volume index was correlated. No TTE parameters were associated with VE/VCO2.

Conclusion:
Notably, echocardiographic stroke volume and tricuspid valve regurgitation peak velocity exhibited a strong correlation with absolute peak VO2/kg and percent predicted peak VO2/kg. LV stroke volume index was correlated with heart rate recovery. VE/VCO2 was not associated with any resting echocardiographic parameters, suggesting this parameter is truly exercise-dependent.
Abstract 4146556: Stratifin is a critical target in Pulmonary Hypertension
Authors: James Joel , Dejesus Vinicio , Rafikova Olga , Rafikov Ruslan
Published: November 2024

Introduction:
Pulmonary hypertension (PH) is a fatal cardiovascular disease marked by extensive vascular remodeling. Pericytes, crucial for capillary function and typically associated with endothelial cells (ECs), are dysfunctional in PH and contribute significantly to vascular remodeling. Our research indicates that Aminopeptidase-N (APN) is overexpressed in the lungs of PH patients, contributing to pericyte proliferation, although the underlying mechanisms remain unclear. We recently discovered elevated stratifin (SFN) levels in the ECs of PH patients. SFN is known to interact with proteins like APN and activate downstream signaling pathways.

Hypothesis:
We hypothesize that elevated SFN binds to pericyte APN, triggering a pathological proliferative response.

Methods:
We utilized rats with the NFU1 (G208C) mutation, which develop spontaneous PH characterized by severe vascular remodeling and increased right ventricular systolic pressure (RVSP). To analyze cell phenotype shifts, we employed scRNA-seq and confocal imaging. Additionally, we used R18, a peptide that inhibits SFN activation of downstream targets, to explore if targeting SFN reverses PH.

Results:
We found elevated circulating SFN levels in PH patient plasma and observed high SFN expression and secretion in isolated ECs from PH patients. NFU1 rats mirrored these findings, showing significantly elevated SFN expression and secretion in ECs. Similarly, increased APN was found in both the lungs of PH patients and the isolated pericytes of NFU1 rats. scRNA-seq followed by Cell-Chat interaction analysis revealed that NFU1 pericytes had reduced interactions with ECs. Additionally, scRNA-seq indicated a shift to a "smooth muscle cell-like" phenotype in pericytes, characterized by increased calponin-3 and SMMHC expression. Confocal imaging confirmed significant disruption of pericyte-EC connections in NFU1 rats. Treatment with R18 in NFU1 rats significantly reversed vascular remodeling and RVSP. Echocardiography showed that R18 significantly improved the ratio of pulmonary acceleration to pulmonary ejection time. Furthermore, scRNA-seq demonstrated that R18 treatment improved pericyte-EC connections and regulated the pericyte phenotype shift in NFU1 rats.

Conclusions:
Endothelial stratifin induces a phenotype shift in pericytes, leading to vascular remodeling and PH. Targeting SFN signaling presents a novel strategy to combat PH.
Abstract 4146562: Diagnosis of Left Ventricular Diastolic Dysfunction using Deep Learning on electrocardiograms
Authors: Shetty Samantha , Lampert Joshua , Jiang Joy , Nadkarni Girish , Vaid Akhil
Published: November 2024

Left Ventricular Diastolic Dysfunction (LVDD) is implicated in conditions with abnormal LV filling and reduced LV distension and relaxation. Classified into grades I to IV, LVDD can be progressive particularly when its underlying cause is not appropriately treated. The prevalence of LVDD varies greatly (10-35%) in the elderly population, likely in the setting of varying inclusion criteria, LVDD grading and definitions. Specifically, LVDD Grade II/III is associated with a higher mortality risk and has been shown to predict major adverse cardiac events including myocardial infarction, heart failure, and all-cause mortality.

Echocardiography (echo) is used to quantify LVDD and its severity. Given its dynamic nature, identifying LVDD and its progression across other diagnostic modalities is vital. One such modality is the electrocardiogram (ECG). Although ECGs are widely accepted for the identification of abnormalities in cardiac conduction, pathology, and structure, some ECG findings may go undetected by human interpreters. Applying machine learning techniques to ECG for detection of LVDD may help address this need.

In this study, we used rule-based Natural Language Processing (NLP) on echo reports to extract cardiologist-confirmed annotations for the presence and grading of LVDD. The NLP pipeline labelled reports as having no LVDD, indeterminate LVDD, or LVDD of grades I, II, or III. These labels were paired to ECG data collected within 7 days of the echo. ECGs paired with an echo of LVDD Grade II were considered cases and were paired to controls matched based on age, sex and race. Patients were excluded if their ECG diagnostic codes indicated conduction abnormalities, concurrent ischemia, and prior intervention. We trained a ConvNeXt Large model capable of processing images of up to 512x512 pixels over 25 epochs against a patient aware 80% training and 20% testing split.

We collected 121,161 ECGs from 27,760 patients with an outcome prevalence of 31.4%. Our model detected patients with LVDD Grade II/III with AUROC of 0.87 (95% CI 0.86-0.87) and AUPRC of 0.82 (95% CI 0.81-0.83) (Figure 1). Saliency heatmaps showed regions around the QRS complex as more important for diagnosis of LVDD (Figure 2).

Our study demonstrates how machine learning can augment clinical practice. Specifically, it may prove to be a useful screening tool for patients at risk of worsening cardiac disease, resource limited areas, and primary care settings in which ECG is readily available.
Abstract 4146602: Deep Learning-enabled Detection of Aortic Stenosis from Noisy Single-lead Electrocardiograms
Authors: Aminorroaya Arya , Dhingra Lovedeep , Pedroso Camargos Aline , Vasisht Shankar Sumukh , Oikonomou Evangelos , Khera Rohan
Published: November 2024

Background:
Despite vast improvements in management strategies, aortic stenosis (AS) remains underdiagnosed, posing a substantial healthcare burden. Deep learning algorithms applied to portable ECGs can enable community screening for AS in older adults. However, noise in portable ECGs often hinders model performance. To address this, we developed and validated a noise-adapted AI algorithm to detect AS from 1-lead ECG and compared it against 12-lead ECGs in a large diverse US health system.

Methods:
Using lead I ECG among individuals with echocardiograms within a 30-day window from 84,438 patients at Yale (2015-2023), we developed a 1-lead AS screening model to detect moderate/severe AS. We validated this in 65,988 patients from 5 geographically distinct affiliated community hospitals and practices. Random Gaussian noise was introduced during training to improve the model’s resilience to noisy acquisition. To enforce learning AS-specific signatures as opposed to confounders, each 1-lead ECG of a patient with AS was matched with 10 controls on age, sex, hypertension, and heart failure. We trained an ensemble deep learning model using 1-lead ECGs, and patients’ age and sex as inputs to detect AS. Using the same strategy, we evaluated the performance of models trained using 12-lead ECGs.

Results:
In the development set, 5.3% had AS compared with 4.5-9.3% across the validation sites. The ensemble 1-lead model achieved an AUROC of 0.845 (95% CI, 0.829-0.862) for detecting moderate or severe AS with consistent performance across community data sources (AUROC: 0.797-0.835). The discrimination of the 1-lead model was comparable to those achieved by 12-lead models (0.864 [0.848-0.879]). The model probability was progressively associated with a higher prevalence of AS (ORs for Q2 vs Q1, 35 [5-254]; Q3 vs Q1, 91 [13-654]; Q4 vs Q1, 388 [55-2,768]). The model output can be optimized to enable either a high sensitivity of >90% (with corresponding specificity of 63%, PPV of 12%, and NPV of 99%) or for specificity of >90% to reduce false positive results (with sensitivity 53%, PPV of 23%, and NPV of 97%).

Conclusion:
A noise-adapted AI model can detect clinically significant AS from 1-lead ECGs, with performance similar to models trained on full 12-lead ECGs. Given its ease of deployment on wearable and portable devices, this represents a scalable screening strategy for asymptomatic AS in the community.
Abstract 4146609: Evaluating the performance and potential bias of predictive models for the detection of transthyretin cardiac amyloidosis
Authors: Hourmozdi Jonathan , Easton Nicholas , Benigeri Simon , Thomas James , Narang Akhil , Ouyang David , Duffy Grant , Okwuosa Ike , Kline Adrienne , Kho Abel , Luo Yuan , Shah Sanjiv , Ahmad Faraz
Published: November 2024

Background:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a highly morbid cause of heart failure (HF). Early detection enables initiation of novel therapies to halt progression and drastically improve outcomes. Current evidence suggests that Black communities are disproportionately impacted by underdiagnosis. Models developed to detect ATTR-CM have been proposed as a screening strategy to address this unmet need, but trust in model outputs and concern for bias remain a barrier to adoption. We externally validated the performance of predictive screening tools and audited the models for bias on a retrospective cohort across a large health system.

Methods:
We identified patients treated at an integrated health system from 2010-2022 with biopsy or PYP scan-confirmed ATTR-CM and age -and sex-matched them to controls with HF in a 19:1 ratio to target 5% prevalence. We then compared the performance of three publicly available algorithms: a random forest model of claims data, the regression-based Mayo ATTR-CM score, and a deep-learning echo model (EchoNet-LVH). Bias was measured in the best performing models using standard fairness metrics.

Results:
We identified 245 confirmed cases of ATTR-CM for 4900 patients total in our analytic cohort. We excluded 892 patients (41 cases) in which EchoNet-LVH could not be run due to image quality or other factors. In the remaining 4008 patients, 78.7% of the cohort self-identified as White, 8.8% Black, 4.0% Hispanic and 8.5% Other. ATTR-CM prevalence was highest in individuals who identified as Black. The claims-based model performed poorly with an AUC of 0.48. EchoNet-LVH had higher AUC (0.88 vs 0.78) and average precision (0.62 vs 0.18) compared to the Mayo score. Results from bias auditing of the top performing models are presented in the Table below.

Conclusions:
In external validation using a large, diverse cohort of patients with heart failure, a deep-learning echo-based model to detect ATTR-CM demonstrated best overall performance compared to two other publicly available models. The results of a bias audit suggest that the model is unlikely to exacerbate existing health disparities through inequitable distribution of error with respect to self-identified Black race.
Abstract 4146613: Dual Trajectories of Allopurinol and Colchicine Use and Cardiovascular Outcomes among Older Adults
Authors: Morris Earl , Lo-CIganic Jenny , Daniels Mike , Segal Richard , Vouri Scott , Smith Steven
Published: November 2024

Background:
Several anti-inflammatory and urate-lowering drugs commonly used in gout have shown promise in reducing cardiovascular risk. However, there remains controversy regarding the benefits of concomitant allopurinol and colchicine in cardiovascular risk prevention, and many previous studies have failed to account for time-varying dose and duration of use for both medications. Thus, we aimed to 1) examine dual trajectories of allopurinol-colchicine use and 2) evaluate risk of major adverse cardiovascular events (MACE) according to trajectories.

Methods:
Using 2011-2020 Medicare claims, we identified new users of allopurinol. We defined the date of first allopurinol fill as the index date and required continuous enrollment in Medicare Parts A. B, and D for 12 months before and after index date Then, we used group-based multi-trajectory modeling to identify allopurinol and colchicine use patterns by calculating average daily dose for each medication separately during each 2-week period during the first 12 months of allopurinol use. We then constructed inverse probability of treatment weighted Cox survival models to compare time-to-incident MACE across trajectories.

Results:
We identified 59,429 beneficiaries (mean age: 73.9; 82.6% non-Hispanic white) and ten unique trajectories including: six trajectories with no colchicine use (Trajectory A-F) and four trajectories with colchicine use (Trajectory G-J). Compared to Trajectory A (rapidly decreasing allopurinol - no colchicine), we observed a lower risk for MACE among Trajectories E (~200 mg allopurinol - no colchicine; aHR: 0.89 [95% CI: 0.87-0.92), F (~300 mg allopurinol - no colchicine; aHR: 0.91 [95% CI: 0.89-0.94]), I (~100 mg allopurinol - ~1.2 mg colchine [stable]; aHR: 0.96 [95% CI: 0.93-0.99]), and J (~300 mg allopurinol - gradually decreasing colchicine; aHR: 0.88 [95% CI: 0.85-0.91]).

Conclusions:
These findings suggest that older adults may benefit from interventions aimed at optimizing dose and duration of allopurinol and colchcine when initiating allopurinol among older adults and further support the need for additional research on the role of concomitant allopurinol and colchicine in cardiovascular risk prevention.
Abstract 4146674: Sex Differences in Readmissions and Outcomes of Medically-Managed Type B Aortic Dissection
Authors: Luna Paulina , Kim Luke K. , Singh Nickpreet , Iranitalab Teagan , Cheung Jim , Devereux Richard , Weinsaft Jonathan , Girardi Leonard , Mecklai Alicia , Ascunce Rebecca , Marcus Julie , Subramanyam Pritha , Krishnamurthy Amrita , Steitieh Diala , Roman Mary , Narula Nupoor
Published: November 2024

Introduction:
Medical management is recommended for patients with acute uncomplicated type B aortic dissection (TBAD), with operative intervention reserved for complicated cases. There is little research focused on sex differences in outcomes in patients with TBAD managed medically.

Research Question:
What is the impact of patient sex on in-hospital outcomes and readmissions for TBAD in patients who are managed medically?

Methods:
Hospitalizations of adults with a diagnosis of TBAD were identified using the 2016-2019 Nationwide Readmissions Database. TBAD diagnosis was deduced by inclusion of dissection of thoracic or thoracoabdominal aorta and exclusion of presumed type A aortic dissection based on prior studies. Hospitalizations associated with endovascular or open repair were excluded. Multivariable logistic regression modeling was used to investigate the association of sex with in-hospital mortality. A Cox proportional hazards model was used to assess the association between sex and readmission rates.

Results:
There were 52,269 TBAD hospitalizations (58% men). Compared to men, women were older (median age 72 vs 65 years), had higher in-hospital mortality (11.5% vs 8.5%), shorter median length of stay (3.95 vs 4.23 days), lower median total charges ($53,461 vs $63,655), and decreased rates of elective admissions (6.4% vs 8.2%) (all p<0.05). Despite similar rates of hypertension, higher rates of atherosclerotic disease and risk factors in men, including coronary artery disease, obesity, and smoking, and decreased rates of hospital-related complications in women, including acute kidney injury, women experienced increased adjusted in-hospital mortality (odds ratio: 1.16; 95% CI, 1.06-1.27). However, there were no sex differences in readmission risk at 30, 90, and 180 days, perhaps reflecting a survivor bias.

Conclusions:
Women with TBAD who were managed medically experienced higher in-hospital mortality than men despite lower rates of atherosclerotic disease and risk factors. Prior research has demonstrated sex-specific differences in demographics and presenting TBAD clinical characteristics, including older age in women, varied signs/symptoms, and delays in diagnosis in women. We speculate that these features may contribute to the worse immediate outcomes observed in women. Further data are needed to delineate additional causes of adverse acute outcomes in women managed medically, including condition- (imaging and anatomic features) and medication-specific factors.
Abstract 4146705: Thrombo-inflammatory biomarker and blood cellular indices are predictive of 30-day mortality Outcome in Patients with Acute Pulmonary Embolism
Authors: Siddiqui Fakiha , Darki Amir , Tafur Alfonso , Kantarcioglu Bulent , Hoppensteadt Debra , Monreal Manuel , Fareed Jawed
Published: November 2024

Introduction:
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is the leading cause of cardiovascular death. The pathophysiology of PE is complex and multifactorial. This study was designed to understand the relationship of thrombo-inflammatory biomarkers including endothelial dysregulation, platelet and coagulation activation, fibrinolysis, and inflammation along with blood cellular indices for 30-day mortality outcome in PE patients.

Materials and Method:
Citrated blood samples from 500 patients with the confirmed diagnosis of PE were collected from Loyola University Medical Center. Biomarkers including vWF, E-Selectin, P-Selectin, FVII, FIX, FX, FXIIIa, D-Dimer, PAI-1a, tPA, TAFIa, CRP, IL-6 and TNF-α were analyzed by Sandwich ELISA method. Blood cellular indices as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and systemic immune-inflammation index (SII; NLR* platelets) were calculated from complete blood count. Thirty-day mortality data was obtained from chart review. Receiver operating curve (ROC) analysis to determine the optimal cutoff values, while for degree of association univariate chi-square and multivariate logistic regression analysis were performed for 30-day morality.

Results:
The study cohort includes 500 patients with equivalent distribution of male (52.1%) and female (47.9%) with the median age of 64-years. In first 30-day, 48 (9.7%) of the patients died. At baseline, patients who subsequently died had higher levels of vWF, P-selectin, tPA, PAI-1a, D-dimer, CRP, IL-6, TNF-α, NLR, PLR, and SII. Following ROC and univariate analysis, all the significant markers and indices were included in the multivariate logistic regression model. Of note, vWF >140 (OR: 2.68; 95%CI: 1.04-6.92), F-X <65 (OR: 4.55; 95%CI: 1.33-15.6), F-XIIIa <58 (OR: 2.70; 95%CI: 1.13-6.47), D-Dimer >13688 (OR: 3.51; 95%CI: 1.32-9.35), CRP >12 (OR: 5.31; 95%CI: 1.01-28.0), TNF-α >2 (OR: 2.65; 95%CI: 1.13-6.19), and NLR >7 (OR: 4.44; 95%CI: 1.76-11.19) predicted risk of 30-day mortality in PE patients (Figure 1).

Conclusion:
This study suggests that patients with vWF >140, FX <65, FXIIIa <58, D-Dimer >13688, CRP >12, TNF-α >2, and NLR >7 at baseline were at increased risk of death in 30-days. Study also suggests the integrated role of thrombo-inflammatory biomarkers and blood cellular indices for the risk stratification and prediction of the adverse outcomes.
Abstract 4146723: Integrating Multi-Omics, Phenotypic, and Social Determinants for Stroke Prediction in Atrial Fibrillation: Advancing Precision Health Using Machine Learning
Authors: Azizi Zahra , Gupte Trisha , Zhou Jiayan , Kho Pik Fang , Guarischi-Sousa Rodrigo , Chen Estella , Panyard Daniel , CLARKE Shoa , Assimes Themistocles
Published: November 2024

Introduction:
Atrial fibrillation (AF) is linked to an elevated risk of ischemic stroke (IS) and mortality. However, the performance of existing clinical scoring systems in assessing these outcomes is at best moderate. The blood proteome serves as a vital indicator of biological processes related to complex disorders. Consequently, there exists an opportunity to enhance the predictive accuracy of such risk scores by incorporating blood proteomic data.

Purpose:
In this study, we aim to evaluate the combined influence of genomics, proteomics, biomarkers, phenotypic, and social determinants of health (SDOH) on AF outcomes to better understand a precision health framework in managing AF.

Methods:
We analyzed patients with AF in the UK Biobank cohort who underwent proteomics measurements using the Olink Proximity Extension Assay. The primary endpoint was the incidence of IS.We assessed the intersection of multi-omics,comorbidities,SDOH and traditional CHA2DS2-VASc score to identify the most important factors associated with IS.We employed multi-step machine learning algorithms to evaluate 3,083 features, including Step1,which involved separate models for each feature type,followed by Step 2,where a combined model was used to assess the complex relationship between these features.The area under the curve (AUC) was used to compare the discriminative ability of the model with the addition of each feature group for predicting IS.Grid search and 10-fold cross-validation were performed to identify the best hyperparameters,and we calculated the mean AUC for the final models.SHAP values were reported for the top 30 features in the final XGBoost model (Figure1).

Results:
Among 4,842 patients with AF(mean age 67.2±9.5 years,61.8% female),5.2% experienced an IS within 9.9±7.5 years after AF diagnosis.The mean CHA2DS2-VASc score was 2.3±1.4, with 60.14% on anticoagulation therapy.The AUC for the CHA2DS2-VASc score at baseline was 0.493.Adding SDOH, polygenic scores, phenotypic data, proteomics, and biomarkers improved the model's discriminative ability (Figure 1.A), with a combined model AUC of 0.619 (95% CI: 0.592-0.645)(Figure 1.B).The top 30 features in the final model, primarily proteins, are shown in Figure 1C.

Conclusion:
A small number of plasma proteins can substantially enhance risk prediction of IS in the setting of AF. Further validation could enable a single-source,personalized assessment of stroke risk in patients with AF as a gateway to personalized risk reduction therapy.
Abstract 4146727: Intensive lifestyle intervention, cardiac biomarkers and atherosclerotic cardiovascular disease in type 2 diabetes and overweight or obesity – a post-hoc analysis of the Look Action for Health in Diabetes (AHEAD) trial
Authors: Patel Kershaw , Chunawala Zainali , Segar Matthew , Garcia Katelyn , Ndumele Chiadi , Wang Thomas , Januzzi James , Butler Javed , Lam Carolyn , Bertoni Alain , Espeland Mark , Pandey Ambarish
Published: November 2024

Introduction:
High-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are associated with atherosclerotic cardiovascular disease (ASCVD) risk in type 2 diabetes (T2D). However, the association of longitudinal changes in these cardiac biomarkers with ASCVD risk in T2D is not well-established. Furthermore, the effects of an intensive lifestyle intervention (ILI) targeting weight loss on cardiac biomarkers is not well-characterized.

Methods:
Participants of the Look AHEAD (Action for Health in Diabetes) trial with T2D and overweight or obesity were included. Hs-cTnT and NT-proBNP were measured at baseline, 1- and 4-year follow-up (Roche Diagnostics). Adjusted Cox models were created to evaluate the associations of baseline, 1-, and 4-year change in cardiac biomarkers with ASCVD risk (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina). The effects of the ILI targeting weight loss versus diabetes support and education (DSE) on cardiac biomarker changes were summarized as the geometric mean ratio (GMR) and 95% confidence interval (CI).

Results:
Among 3,984 participants with available cardiac biomarker data, there were 771 ASCVD events (median follow-up: 12 years). Higher hs-cTnT and NT-proBNP at baseline were each significantly associated with higher ASCVD risk (
Figure 1A
). Changes in hs-cTnT and NT-proBNP over 1-year follow-up were not significantly associated with ASCVD risk. However, sustained increases in hs-cTnT and NT-proBNP over 4-year follow-up were each significantly associated with higher ASCVD risk. The ILI versus DSE was significantly associated with lower hs-cTnT at 1- and 4-year follow-up (GMR [95% CI]: 0.96 [0.93-0.99] and 0.94 [0.92-0.97]), respectively) (
Figure 1B
). In contrast, NT-proBNP increased with the ILI (vs. DSE) at 1-year (GMR [95% CI]: 1.11 [1.05-1.17]), but this difference was attenuated and no longer significant at 4-years.

Conclusions:
Among adults with T2D, sustained increases in hs-cTnT and NT-proBNP over 4-year follow-up were associated with higher ASCVD risk. An ILI targeting weight loss led to a significant reduction in hs-cTnT and transient rise in NT-proBNP that attenuated over time.
Abstract 4146762: Cardiac Inflammation as a Key Driver of Desmoplakin-Mediated Cardiomyopathy: Insights from a Novel Animal Model
Authors: Gutierrez Lara Erika Joana , Zhang Jing , Liang Yan , Ninh Van , Gu Yusu , King Kevin , Sheikh Farah
Published: November 2024

Cardiac inflammation is increasingly recognized as an important aspect of arrhythmogenic right ventricular cardiomyopathy (ARVC), a genetic cardiac disease characterized by loss of cardiomyocytes and their gradual replacement by fibro-fatty tissue, resulting in cardiac dysfunction and sudden cardiac death. Mutations in desmosomal genes, which serve as essential mechanical anchors between cardiac muscle cells, are a principal cause of ARVC. Patients with mutations in the desmosomal gene, desmoplakin (
DSP
) exhibit a distinct cardiomyopathy, marked by its strong association with myocarditis and recurrent inflammatory episodes, leading to aggravated cardiac outcomes. However, the precise role of inflammation in driving of
DSP
-mediated cardiomyopathy remains to be fully elucidated. We hypothesize that
DSP
deficiency alters the cardiomyocyte response to acute inflammatory response, leading to chronic immune intolerance and ultimately triggering ARVC disease progression. To test our hypothesis, we subjected cardiac-specific
DSP
heterozygous (DSP Het) deficient mice, which displayed 50% loss in DSP protein levels and remained asymptomatic for a year, to an acute immunological challenge. This allowed us to evaluate the chronic impact on ARVC pathogenesis in the absence of pre-existing cardiac disease. Our findings reveal that acute immunological challenge in DSP Het mice elicits a destructive cardiomyocyte immune response, akin to fulminant myocarditis. Furthermore, this acute challenge is sufficient to induce classic ARVC features in DSP Het deficient mice as exemplified by: (i) enlarged heart size and ventricular chambers, (ii) fibrotic remodeling, (iii) epicardial fat tissue accumulation, with pronounced effects on the right ventricle. Additionally, we observed electrophysiological deficits, such as premature ventricular contractions and QRS prolongation, along with functional deficits associated with bi-ventricular form of ARVC, albeit with a greater impact on the right ventricle. Single nuclei RNA sequencing studies in mice revealed the presence and differences in T cell populations in hearts from mice with DSP-related myocarditis, indicating early immune antigen recognition as a potential mechanism driving disease. These studies suggest that the immune system may be an important driver of ARVC pathogenesis in patients with underlying desmosomal gene mutations, such as DSP, especially in the setting of autosomal dominant genetics.
Abstract 4146813: Evaluating the Prevalence of Optimal Neurodevelopmental Outcome at 2 Years in Children Previously on VAD Support
Authors: Conway Jennifer , Buchholz Holger , Freed Darren , Al Aklabi Mohammed , Jonker Devilliers , Joffe Ari , Urschel Simon , Pidborochynski Tara , Atallah Joseph , Robertson Charlene
Published: November 2024

Background:
Ventricular assist devices (VADs) are becoming a standard part of advanced heart failure therapy in children. They are utilized mostly as a bridge to transplant (HTx) but also can be used for recovery. While information on complications during VAD therapy is available, there is limited information on long term outcomes in this patient population, specifically neurodevelopmental outcomes.

Research Question:
To determine the prevalence of ‘optimal neurodevelopmental outcomes’ in 2-year-old children previously treated with a VAD.

Methods:
Patients were followed through the Complex Pediatric Therapies Follow-Up Program. This study included patients born between January 2006 and December 2022, implanted with a VAD at
<
15 months of age and surviving to 2 years of age. A modified optimal neurodevelopmental outcome was defined as the Cognitive, Language and Motor Composite Scores on the Bayley Scales of Infant and Toddler Development and the Adaptive Behaviour Assessment System - General Adaptive Composite Score ≥ 80 each, with the absence of cerebral palsy, permanent hearing loss, visual impairment, or seizure disorder.

Results:
There were 56 patients who met inclusion criteria with 40 patients surviving to the age of 2 years. Of the survivors, the median (IQR) gestational age (GA) was 38 [37, 39] (4 [7.1%] <37completed weeks GA), 70% were male and 7.5% had a chromosomal abnormality. The median age of implant was 0.39 [0.19, 0.64], years and weight 5.8Kg [4.1, 7.5]. The majority of patients did not have congenital heart disease (62.5%). The most common implant strategy was a left VAD (87.5%) with paracorporeal continuous support (42.5%). Most patients were supported with ECMO (55%) pre- or post-VAD implant. One-third of the cohort had a neurological insult either pre- or post-implant. Total duration of support was a median 32 days [8, 93] with 65% undergoing HTx and 35% decannulated for recovery. Thirty-nine patients underwent full neurodevelopmental testing at 2 years of age with only 25.6% (n=19) of the patients classified as having an optimal neurodevelopmental outcome with 43.6% (n=17) having a Bayley cognitive score <80.

Conclusion:
Optimal neurodevelopmental outcome at 2 years of age was present in only one-quarter of children following a treatment pathway that included VAD therapy in infancy. Important next steps will be to identify associations, including modifiable risk factors, for optimal neurodevelopmental outcomes.
Abstract 4146814: Heart failure is time-dependent and associated with heart transplant, hepatocellular carcinoma, and death in the Fontan population
Authors: Ivey Lindsey , Raskind-Hood Cheryl , Haffner Alexandra , Guo Yuting , SARKER ABEED , Rodriguez Fred , Book Wendy
Published: November 2024

Background:
The Fontan operation has been an effective treatment plan for patients with single ventricle anomalies, greatly improving survival into adulthood. Yet, Fontan patients are at increased risk of numerous cardiac and noncardiac complications, and premature mortality.

Methods:
A cohort of 735 patients with a prior Fontan surgery (median age 7.6yrs at first encounter, 57.4% male, 41.0% Black), with at least one healthcare encounter from a pediatric or adult healthcare system between 2010-2019, was linked to encounter data and death certificates. Heart failure (HF) was defined by ICD-9-CM and ICD-10-CM codes determined by clinicians. The primary composite outcome included heart transplant, hepatocellular carcinoma (HCC) and death. Hospitalizations were defined as an inpatient encounter spanning at least two consecutive days. Time to event was anchored at initial encounter.

Results:
Characteristics of those with and without HF are seen in Table 1. Median age was 17.1yrs [3.0-70.5] and 5.5yrs [3.0-56.0] for those with and without HF, respectively. The composite outcome occurred in 85 Fontan patients (11.6%) at median 3.26yrs after initial encounter. Of those with HF, 12.5% experienced a heart transplant compared to 0.9% without HF (p<0.001), 3.0% with HF had HCC vs 0.5% without HF (p<0.05), and 9.4% with HF died at mean age 29.3yrs compared to 2.7% without HF at mean age 16.3yrs (p<0.001). Kaplan-Meier event-free survival curves appear in Figure 1. Of those with HF, 69.0% were hospitalized at least once compared to 53.0% of those without HF (p<0.001). Fontan patients without HF were 95.9% likely to be event-free at 5yrs follow-up compared to those with HF who were 84.7% likely to be event-free at 5yrs.

Conclusion:
Fontan patients more commonly experience HF at older ages. HF is associated with heart transplant, HCC, and death during follow-up compared with Fontan patients without HF. Hospitalizations were common in both groups, but occurred more commonly with HF.
Abstract 4146883: Analysis of Near-Infrared Spectroscopy Vascular Occlusion Test as a Complement to Ankle-Brachial Index and 6-Minute Walk Test in Patients Diagnosed with Peripheral Artery Disease
Authors: Rodriguez Cesar , Lanka Santh Prakash , Maraj Joshua , Alsabbagh Yaman , Farres Sam , Ade Carl , Liu Xiuwen , Delp Judy
Published: November 2024

Introduction:
Peripheral arterial disease (PAD) is caused by a lack of blood flow to the musculature relative to its metabolism which results in pain. PAD impacts up to 20% of patients around the world. PAD involves macrovascular and microvascular dysfunction. Near-infrared spectroscopy (NIRS) measures muscle oxygenation levels and assesses microvascular function. The standard of care for diagnosing PAD is the ankle-brachial index (ABI), which assesses macrovascular disease, and the 6-minute walk test (6MWT), which measures gait speed and claudication. NIRS has the potential to monitor progression of PAD.

Hypothesis:
NIRS measurement of muscle oxygenation, during a standard test of vascular occlusion and post-occlusive hyperemia, the vascular occlusion test (VOT), is predictive of PAD severity as determined by ABI and 6MWT.

Methods:
We studied 24 patients diagnosed with PAD. The mean age of the patients was 71.3 years, including 54% (n=13) males and 46% (n=11) females. The VOT consisted of rest, occlusion, and reperfusion phases each lasting 5 min (15 min total). Muscle oxygen saturation levels were recorded at 2 hertz. For every patient, 6 features were extracted from the VOT data using computational methods. The VOT features from 15 patients were used to train function-fitting neural network models to predict ABI and 6MWT Continuous Distance. The models were then used to predict ABI and 6MWT Continuous Distance from the VOT features of 9 test patients not used in the training,

Results:
For patients in the test set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 14%±13% and 15%±17%, respectively (Figure 1). For patients in the training set, the ABI and 6MWT Continuous Distance predicted by the models differed from the actual measurements by 0±0% and 12%±11%, respectively (Figure 1).

Conclusion:
The VOT has the potential to predict the ABI and 6MWT Continuous Distance of patients diagnosed with PAD, suggesting that the VOT can be automated and used to monitor the severity of PAD. With more data from both healthy patients and PAD patients, and improvement of the model, we anticipate that the VOT will complement ABI and 6MWT in the diagnosis and monitoring of PAD.
Abstract 4146888: Safety report from a remote disease management program to improve sodium glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonist prescribing in Type 2 diabetes
Authors: Hassan Shahzad , Chang Lee-Shing , Gabovitch Dan , Stern Gretchen , Chasse Jacqueline , Zelle David , Colling Caitlin , Aronson Samuel , Figueroa Christian , Collins Emma , Ruggiero Ryan , Gaziano Thomas , Plutzky Jorge , Cannon Christopher , Wexler Deborah , Scirica Benjamin , Blood Alexander
Published: November 2024

Introduction:
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) offer cardiovascular (CV) and kidney protective effects in patients with Type 2 DM (T2DM). Despite the benefits, these medications are underutilized due to various barriers. Remote management programs present a scalable solution to improve uptake of these medications in accordance with guidelines. However, safety concerns may limit the adoption of such programs. We report adverse effects (AEs) and safety outcomes in participants who initiated either medication class within a remote program.

Methods:
The Diabetes Remote Intervention to improve the use of Evidence-based medications (DRIVE) Program was a randomized study conducted at Mass General Brigham (MGB), tertiary care medical center. The aim of study was to initiate SGLT2i or GLP-1 RA in T2DM patients with or at higher risk of CV and/or kidney complications. A total of 200 participants were enrolled in 2-months of Education-first or Simultaneous Education and medications initiation arm, with 106 starting SGLT2i or GLP-1 RA treatment within six months of enrollment. Study staff regularly contacted participants who were initiated on either medication to assess AEs and safety outcomes.

Results:
Of 68 participants who started on an SGLT2i, 35 (51.5%) experienced any AE, 8 (11.8%) had a genitourinary AE and 7 (10.3%) experienced an AE that led to discontinuation of drug. Of 40 participants who started on a GLP-1 RA, 22 (55.0%) experienced any AE, 19 (47.5%) had a gastrointestinal AE and 4 (10.0%) experienced an AE that led to discontinuation of drug. Nearly all medication-related AEs were managed by DRIVE program clinicians independently or in collaboration with participant’s outpatient clinical team.

Conclusion:
The DRIVE program safely initiated and managed SGLT2i or GLP-1 RA treatment in participants. The rates of AEs observed were comparable to those reported in clinical trials, supporting the scalability, effectiveness, and safety of remote initiation and management of these drugs. Furthermore, AEs from these medications can be successfully managed remotely by a clinical team in conjunction with participants’ primary providers.