bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4147589: Heart Rate Variability as a Predictor of Postoperative Outcomes in Congenital Heart Surgery
Authors: Vaida Mia , Feins Eric , Kheir John , Triedman John , Newburger Jane , Dionne Audrey
Published: November 2024

Background:
Reduced heart rate variability (HRV) reflects sympatho-vagal imbalance and is associated with cardiovascular mortality in adults. Literature is limited in pediatrics, but reduced HRV has been observed in congenital heart disease (CHD) and is associated with prolonged postoperative hospitalization.

Objective:
To investigate the effect of HRV metrics on outcomes after surgery for CHD.

Methods:
This single-center retrospective cohort study included children aged 0-18 years who underwent surgery for CHD (2010-2018). Preoperative 12-lead ECGs (within 10 days) and the first postoperative ECGs were analyzed. ECGs with atrial or ventricular pacing were excluded. Ultra-short term HRV metrics were calculated, including standard deviation of interbeat intervals (SDNN) and the root mean square of successive RR interval differences (RMSSD). SNDD and RMSSD were classified as low if <25
th
percentile. Post-operative complication was defined as CPR, unplanned open chest, unplanned reoperation, low cardiac output, bleeding, extracorporal membrane oxygenation (ECMO) or death prior to hospital discharge. Major adverse cardiac event (MACE) was defined as CPR, ECMO and/or death. All analysis were adjusted for age and gender.

Results:
Among 7,192 children undergoing surgery (55% male, age 0.9 [0.2, 4.5] years), 2,413 (34%) experienced postop complications, 344 (5%) MACE, and 270 (4%) died prior to hospital discharge. HRV metrics could be calculated in 3347 (47%) patients pre-operatively and 3392 (47%) post-operatively. SDNN and RMSS were 0.012 [0.005, 0.028] ms and 0.010 [IQR 0.005, 0.029] ms pre-operatively, and 0.002 [0.002, 0.005] ms and 0.003 [IQR 0.002, 0.005] ms post-operatively. Pre-operative low SDNN and RMSSD were associated with increased risk of post-operative complications, MACE, and death prior to hospital discharge (Figure). Low post-operative RMSS was associated with MACE and death prior to hospital discharge. Low pre- and post-operative SDNN and RMSSD were associated with prolonged CICU and hospital length of stay.

Conclusion:
Low HRV metrics were associated with worse post-operative outcomes. Pre-operative HRV metrics were most predictive of post-operative complications and mortality.
Abstract 4147592: Acute Pressor, Chronotropic and Adrenergic Effects of Adderall - A Randomized Double-Blind Placebo Controlled Crossover Study
Authors: Somers Kiran , Bock Joshua , Covassin Naima , Bukartyk Jan , Rajendran Aiswarya , Svatikova Anna
Published: November 2024

Introduction:
Adderall, the brand name for a combination of dextroamphetamine and amphetamine salts, is used to treat attention deficit disorder and narcolepsy, but is widely abused for improving cognitive function and alertness in absence of a medical indication. While little is known of its acute cardiovascular (CV) physiologic effects, Adderall has been linked to acute CV events (myocardial infarction, tachyarrhythmias, heart failure, Takotsubo cardiomyopathy and sudden death) and to long term CV consequences including hypertension and arterial disease.

Aim:
To examine the acute CV responses to Adderall in healthy subjects not on stimulant therapy in a randomized double-blind placebo-controlled crossover study. (CT.gov NCT02979327)

Methods:
Thirty subjects were randomized to 25 mg Adderall versus placebo. We measured supine resting blood pressure (BP), heart rate (HR), and plasma catecholamines, before and 3 hours after consuming Adderall or placebo.

Results:
Twenty-nine subjects (16 females; aged 25±5 yrs) completed both Adderall and placebo conditions, with a median of 10 days between visits. Systolic BP (SBP) increased from 112±10 mmHg to 127±11 mmHg after use of Adderall but was unchanged before vs after placebo drug intake (112±8 mmHg and 112±9 mmHg respectively; group by time interaction p<0.01). Diastolic BP and mean BP increased by 6.8 mmHg and 8.5 mmHg respectively and HR increased by 7.3 beats/min with Adderall, but they did not change with placebo (p<0.01). Plasma norepinephrine increased from 217±79 pg/ml before to 323±105 pg/ml after Adderall but was unchanged after placebo (p<0.05) (Figure 1).

Conclusions:
Healthy subjects consuming a modest dose of Adderall manifest striking increases in BP, HR and sympathetic activation, even during supine rest. These findings may have important mechanistic implications for understanding acute CV events and long-term risk of CV disease associated with stimulant medications.
Abstract 4147596: Investigating the Role of
EMILIN1
in Thoracic Aortic Aneurysm Using Vascular Smooth Muscle Cells
Authors: Schwartzman William , Lee Vivian , Barry Aurelie , Bektik Emre , Feinberg Mark , Gupta Rajat
Published: November 2024

Background:
Thoracic aortic aneurysm and dissection (TAAD) is a rare but devastating disorder that affects more than 13,000 people per year in the United States. Genetic testing can help guide early detection and therapy, but despite identification of numerous causal loci, the genetic architecture of TAAD remains poorly understood. There is a need for further investigation to identify and confirm new causal genes to improve screening for TAAD. We hypothesize that genetic testing of the most phenotypically severe cases in pediatric patients will improve the yield of novel gene identification.

Methods:
We identified an extreme case of TAA in a 6-month-old patient at Boston Children’s Hospital and performed whole-exome sequencing on DNA samples collected from the proband and unaffected parents. We generated a clonal
EMILIN1
knockout (KO) human aortic vascular smooth muscle cell (VSMC) model using CRISPR/Cas9 to assess the effect of complete
EMILIN1
loss on gene expression, protein level, and critical VSMC functions including contractility, migration, and proliferation by collagen disk assay, scratch assay, and Ki67 staining respectively.

Results:
Whole exome sequencing in a pediatric patient with an extreme, progressive TAA phenotype (4.0cm, Z-score +15) identified compound heterozygous nonsense mutations in
EMILIN1
, each inherited from one parent, as candidate causal variants. These variants (c.664C>T and c.1606C>T) were validated by Sanger sequencing. The
EMILIN1
KO VSMCs demonstrated marked alterations in expression of genes encoding contractile apparatus and extracellular matrix proteins. Functional tests also revealed increased contractility (p=0.0374), decreased proliferation (p<0.0001), and decreased migration (p<0.0001) of
EMILIN1
KO cells.

Conclusion:
Whole exome sequencing in a 6-month-old patient with a severe presentation of TAA identified likely pathogenic compound heterozygous mutations in the
EMILIN1
gene. Complete
EMILIN1
loss-of-function in VSMCs results in cellular phenotypes comparable to other pathogenic TAA mutations.
Abstract 4147650: Right Ventricular Hemodynamics in Patients Screened for HFpEF with a Novel Artificial Intelligence Screening Tool
Authors: Chang Kevin , Sachar Ryan , Latz Maria , Allen Tess , Blair John , Kim Gene , Grinstein Jonathan , woodward gary , Lang Roberto , Belkin Mark
Published: November 2024

Background:
Invasive hemodynamics are the gold standard for diagnosis of heart failure with preserved ejection fraction (HFpEF). A novel, FDA-approved artificial intelligence (AI) technology that uses a single, 4-chamber transthoracic echocardiogram (TTE) image to screen patients for HFpEF shows promise as a non-invasive tool to assist in diagnosis. Development of right ventricular (RV) dysfunction is a sign of a more advanced HFpEF. Advanced RV hemodynamic parameters, beyond pulmonary arterial pressures (PAP), have not been well studied in HFpEF. We sought to correlate advanced RV hemodynamic parameters in patients screened for HFpEF with this AI screening tool.

Method:
We retrospectively evaluated two cohorts of patients with suspected HFpEF that underwent TTE and RHC at our institution. The most recent TTE for each patient was screened using the AI-based analysis tool and was reported as either “suggestive” or “non-suggestive” of HFpEF – labeled as “positive” or “negative,” respectively. Mean PAP, pulmonary vascular resistance (PVR), pulmonary artery pulsatility index (PAPI), RV cardiac power output (RV-CPO), RV myocardial performance score (RV-MPS), and right atrial pressure to pulmonary capillary wedge pressure ratio (RA:PCWP) were calculated using invasive hemodynamic parameters at rest, and exercise when available. RV-CPO was calculated as [(mean PAP-RAP) x cardiac output] /451, and RV-MPS was calculated as (RV-CPO x PAP)x1.5. Median values were calculated. AI positive and negative groups were compared using Student’s t-test.

Results:
A total of 47 patients (82% women, 79% Black, average EF 62%) were included, with 23 undergoing subsequent exercise RHC. There were 18 (38%) that screened positive for HFpEF, and 29 (62%) screened negative by TTE AI software. Positive patients had a significantly higher mean PAP (median 31 vs 23 mmHg, p=0.01), PVR (2.1 vs 1.3 WU, p=0.02), and RV-CPO (0.26 vs. 0.17, p=0.04) than patients who were screened negative. There were no significant differences in PAPI, RV-MPS, and RA:PCWP at rest. There were no significant differences in mean PAP, PVR, PAPI RV-CPO, RV-MPS, or RA:PCWP with exercise.

Conclusion:
Patients screened positive for HFpEF by a novel AI TTE software had significantly higher PAP and RV-CPO at rest, but no differences in PAPI, RV-MPS, or RA:PCWP ratio. This tool may help identify more advanced HFpEF.
Abstract 4147657: Are Females More Fraily than Males at Time of Heart Failure Diagnosis?
Authors: Roberts Davis Mary , Dieckmann Nathan , Chien Christopher , Hansen Lissi , Erickson Elise , Alkayed Nabil , Shannon Jackilen , Denfeld Quin
Published: November 2024

Background:
In chronic heart failure (HF), physical frailty is more prevalent in females than males, and studies have shown that frailty is associated with worse symptoms. However, sex differences in frailty at the time of HF diagnosis are not well understood, including associations with symptoms.

Research Question:
What are the relationships between frailty, sex, and symptom burden at the time of initial HF diagnosis?

Aims:
1) to quantify sex differences in frailty at the time of HF diagnosis, and 2) to determine if sex influences the association between frailty and symptoms at time of HF diagnosis.

Methods:
This was an analysis of data collected from a study of symptoms among patients with a new diagnosis of Stage C HF and New York Heart Association (NYHA) Functional Classification I-IV symptoms. Frailty was measured using the FRAIL Scale (Fatigue, Resistance, Ambulation, Illnesses,&Loss of Weight). Symptom burden was measured using the Heart Failure Somatic Perceptions Scale (HFSPS). We used comparative statistics to examine differences in frailty (frail vs. robust or pre-frail) by sex, age, and HFSPS score. Then, we used robust linear regression with an interaction between sex and frailty to examine the relationship between HFSPS score and frailty.

Results:
The sample (n=50) was 58.2±16.4 years old, 46% female, and 63% NYHA Classification III/IV. There were no sex differences in HF type, with the majority of participants with HF with reduced ejection fraction (n=38 (67%)). Females were more likely to be frail than males (n=16 (67%), p=0.005, Cohen’s
d
=.85). Age was not significantly different between those who were frail or not. Frail participants reported higher symptom burden in the HFSPS (=47.4±20.8) compared to those who were not (=35.8±21.9), t(48)=-1.91, p=0.06, Cohen’s
d
=-.54). Frailty, sex, and age accounted for 17.1% of the variability in HFSPS (F(4, 45)=2.54, p.05). Individuals who were frail were significantly more symptomatic as measured by the HFSPS (β=22.8± 9.6; 95%CI (3.3, 42.2)), controlling for sex and age. There was a not a significant interaction between frailty and sex (b=20.2, 95% CI (-44.9, 4.5)).

Conclusions:
At the time of HF diagnosis, female patients are more frail and frail patients are more symptomatic, but sex does not moderate the relationship between frailty and symptoms. Larger studies of the role of sex in frailty and symptoms in new HF may contribute to more timely diagnosis and treatment, particularly in females.
Abstract 4147663: Higher LDL Across Lifespan Among Women: A Real-World Analysis
Authors: Nadar Priyanka , Gupta Prerna , Simon Steven , Kao David , Rosenberg Michael
Published: November 2024

Introduction:
Lower low-density lipoprotein (LDL) leads to greater cardiovascular disease risk reduction over the lifespan. Despite this, women are less likely to reach guideline-recommended LDL goals, perhaps due to bias in statin prescription or statin intensity. and disparities in adherence. There are known sex differences in cardiovascular disease and statin response, but little is known about how these differences manifest under real-world conditions.

Aim:
We aim to characterize long-term LDL between men and women who have been prescribed statin therapy as a function of age at initial statin therapy.

Methods:
We retrospectively identified patients within the UCHealth electronic health record among adults from 2012 to 2023 prescribed a statin with at least 3 LDL levels. Patients prescribed concomitant lipid-lowering agents were excluded. We performed a multivariate linear regression model to predict long-term average LDL between genders, adjusting for age at the time of statin prescription, race, ethnicity, BMI, interval from statin prescription, creatinine, and the following diagnoses: diabetes mellitus, ischemic heart disease, ischemic stroke, and smoking history.

Results:
Among 75,276 encounters, 14,902 patients had at least 3 LDL-C measurements and an interval statin initiation. Post-treatment LDL was obtained 212 (± 177) days after statin initiation. The cohort was 49% (7,303 patients) female, with 86% (12,819) white, 4% (648) African American, and 8% (1,249) Hispanic patients. At age 30, men started on statin therapy had a predicted LDL of 117 (95% CI: 114-121 mg/dL), whereas women began with a predicted LDL of 115 (95% CI: 112-119 mg/dL). At age 70, that value was 94.1 (95% CI: 93.4-94.8 mg/dL) among men vs 105.6 (95% CI: 104.9-106.3 mg/dL) in women (Figure).

Discussion:
In this single-center, retrospective observational study, we found that women had a higher predicted LDL compared to men across the lifespan, with a greater difference in those whose first prescription was at an older age. More work is needed to determine if this reflects less aggressive treatment of women than men. Further research needs to be done to bridge this gap in therapy.
Abstract 4147664: Retrieval-Augmented Generation for Extracting CHADS-VASc and HAS-BLED Risk Factors from Unstructured Clinical Notes in Patients with Atrial Fibrillation
Authors: Adejumo Philip , Thangaraj Phyllis , Vasisht Shankar Sumukh , Khera Rohan
Published: November 2024

Background:
Assessment of stroke and bleeding risk in patients with atrial fibrillation (AF) is crucial for guiding anticoagulation therapy. CHADS-VASc and HAS-BLED are widely used scores for defining these risks, but current assessments rely on manual calculation by clinicians or approximations from structured EHR data elements. Unstructured clinical notes contain rich information that could enhance risk assessment. We developed and validated a Retrieval-Augmented Generation (RAG) approach to extract CHADS-VASc and HAS-BLED risk factors from unstructured notes in patients with AF.

Methods:
We employed a RAG architecture paired with the large language model, Llama3, to extract features relevant to CHADS-VASc and HAS-BLED scores from unstructured notes. The model was deployed on a random set of 1,00 clinical notes (416 AF patients) from Yale New Haven Hospital. To establish a gold standard, 2 clinicians manually reviewed and labeled CHADS-VASc and HAS-BLED risk factors in a random subset of 200 notes. The CHADS-VASc and HAS-BLED scores were calculated for each patient using structured data alone and by incorporating risk factors identified with RAG. We assessed performance across risk factors using macro-averaged area under the receiver operating characteristic (AUROC).

Results:
The RAG model demonstrated robust performance in extracting risk factors from clinical notes. In the 1000 clinical notes, RAG identified several risk factors more frequently than structured elements, including hypertension (59.7% vs 46.6%), stroke (19.2% vs 12.7%), vascular disease (35.6% vs 27.2%), diabetes (33.9% vs 27.8%), medication usage predisposing to bleeding (29.1% vs 20.9%), and alcohol use (14.4% vs 8.9%). The RAG approach achieved an accuracy of 91% and macro-AUROC of 0.88, significantly outperforming structured data (accuracy 78%, macro-AUROC 0.76) in 200 expert annotated notes. Incorporating risk factors identified by RAG increased both CHADS-VASc and HAS-BLED scores compared with using structured data, with the mean CHADS-VASc score increasing from 3.3 ± 1.9 using structured data to 4.2 ± 2.1 with RAG. Similarly, the mean HAS-BLED score increased from 2.2 ± 1.3 to 2.7 ± 1.5.

Conclusion:
An LLM-optimized RAG can accurately extract CHADS-VASc and HAS-BLED risk factors from unstructured clinical notes in AF patients. This approach can enable computable risk assessment and guide appropriate anticoagulation therapy.
Abstract 4147667: Elevated Hsp70 Does Not Rescue BAG3 Levels After Hypoxia-Reperfusion Stress or Ischemia-Reperfusion Injury
Authors: Sherer Laura , Zied Ahmed , Martin Thomas , Door Michaela , Delligatti Christine , Kirk Jonathan
Published: November 2024

The co-chaperone BAG3 is critical for protein quality control at the cardiac sarcomere. BAG3 binds to Hsp70 and coordinates the assembly of the CASA (chaperone-assisted selective autophagy) complex, thus supporting proteostasis and cardiomyocyte contractility. BAG3 mutations and/or decreased BAG3 levels are associated with cardiomyopathies, whereas BAG3 overexpression rescues ventricular function after myocardial infarction in mice. Despite BAG3’s promise as a therapeutic target, the mechanisms underlying BAG3 regulation are largely unresolved. Here, we investigate the mechanisms of BAG3 downregulation after stress. We found that BAG3 protein is reduced in human dilated cardiomyopathy hearts compared to non-failing hearts, yet there is an increase in
bag3
mRNA transcript, suggesting BAG3’s downregulation in heart disease may be controlled post-transcriptionally. To identify these post-transcriptional pathways, we subjected neonatal rat ventricular myocytes (NRVMs) to prolonged hypoxia-reoxygenation (H/R) stress, which recapitulated the decrease in BAG3 levels observed in human heart disease. Notably, disrupting Hsp70 binding to BAG3 in NRVMs via the drug JG-98 decreases BAG3’s half-life by ~90%, suggesting that Hsp70 protects BAG3 from degradation. Loss of Hsp70-mediated protection could contribute to declining BAG3 levels, so we quantified Hsp70 abundance after H/R stress in NRVMs, finding no significant change. We also found that overexpressing inducible Hsp70 did not rescue BAG3 levels. To examine BAG3 regulation
in vivo,
we subjected wildtype mice to ischemia-reperfusion injury. After 24 hours, male mice had no change in Hsp70 abundance in the left ventricle, whereas Hsp70 was significantly upregulated in female mice. Despite this difference in Hsp70, BAG3 levels were decreased by ~20% in both sexes. Thus, our
in vivo
and
in vitro
data both suggest that BAG3 downregulation is not caused by loss of Hsp70 binding/protection. Interestingly, the decline in full-length BAG3 (85 kDa) was accompanied by an increase in a BAG3 cleavage product at 74 kDa. We analyzed this product via mass spectrometry, discovering that it lacks a third of the WW domain, which is involved in autophagy. In future experiments, BAG3 cleavage will be explored as a potential mechanism of BAG3 loss. Such mechanisms will provide insight into how to maintain BAG3 levels, and thus cardiac function, during stress.
Abstract 4147668: Impact of New Onset Atrial Fibrillation on In-Hospital Mortality and Other Outcomes Among Patients Admitted for STEMI: A 5-Year Analysis from the National Inpatient Sample
Authors: Wardhere Abdirahman , Nso Nso , Nor Mohammed , Mohamoud Abdilahi , Bampatsias Dimitrios
Published: November 2024

Introduction:
New onset atrial fibrillation (NOAF) is not a so rare condition among patients hospitalized for ST-segment elevation myocardial infarction (STEMI). However, it’s short-term prognostic value have not yet been studied using a large real-world data.

Aim:
To evaluate in-hospital mortality and other clinical outcomes of this high-risk subgroup of patients using a large US real-world data.

Methods:
Between January 2017 and December 2021, 855,400 STEMI patients were identified from the NIS database using ICD-10 codes. The cohort was divided into two groups: those with NOAF and those without (non-NOAF). Outcomes studied included in-hospital mortality and complications such as cardiac arrest, cardiogenic shock requiring pressors or mechanical circulatory support (MCS), acute stroke, and gastrointestinal bleed. Categorical variables were presented as percentages, and continuous variables as median ± interquartile range. Outcomes were analyzed using univariate and multivariate logistic regression to adjust for potential confounders.

Results:
Of the 855,400 STEMI patients, 51,845 (6%) developed new-onset atrial fibrillation (NOAF) during hospitalization. NOAF patients were generally older (70 vs. 63 years), more likely to be women (32.9% vs. 30%), and more often Caucasian. They also had higher rates of COPD (24.6% vs. 12.3%) and valvular diseases (13.8% vs. 8.2%) compared to non-NOAF patients. Univariate analysis showed NOAF was linked to worse outcomes. Multivariate logistic regression, adjusting for age, gender, race, insurance type and comorbidities, revealed NOAF patients had twice the risk of in-hospital mortality (OR: 2.08, CI: 1.96-2.21, P<0.001) and higher odds of complications: cardiac arrest (OR: 1.9, CI: 1.8-2.19, P<0.001), cardiogenic shock requiring MCS (OR: 2.15, CI: 1.94-2.39, P<0.001), stroke (OR: 1.36, CI: 1.19-1.56, P<0.001), and gastrointestinal bleed (OR: 1.56, CI: 1.4-1.74, P<0.001).

Conclusions:
In this retrospective study, developing NOAF during index hospitalization for STEMI was associated with higher risk of in-hospital mortality and developing serious complications. Therefore, clinicians should recognize as a sign of worse prognosis and treat NOAF as soon as possible.
Abstract 4147676: Outcomes Of Chronic Total Occlusion Of Coronary Artery Compared Between Urban And Rural Hospitals In The United States
Authors: sattar yasar , Rao Adishwar , Abdul Basit Salman , Naveed Muhammad Abdullah , Saifuddin Mohammed , Hassan Hafeez
Published: November 2024

Background:
Chronic total occlusion (CTO) of the coronary artery is a complex condition necessitating special care, and the prognosis may vary due to differences in technical and human resources between urban and rural hospitals.

Aim:
To evaluate differences in mortality and cardiovascular outcomes in hospitalizations for CTO at urban centers compared to rural centers.

Methods:
We queried the National Inpatient Sample (NIS) database from 2016-2021 for hospitalizations related to CTO using the ICD-10 CM code I2582. We compared baseline characteristics and outcomes between urban and rural hospitals using Pearson Chi-Square test and two-sample t-test or Wilcoxon Rank Sum test. We also computed adjusted odds ratios (aORs) using multivariate logistic regression models and conducted a sensitivity analysis using 1:1 propensity score matching.

Results:
Out of 562,880 weighted hospitalizations for CTO, patients admitted to urban centers were younger (mean age 67.78 y vs 68.40 y, p<0.001), more likely to be Black American (10.2% vs 6.4%, p<0.001) or Hispanic (10.2% vs 6.4%, p<0.001), had a longer duration of hospital stay (median 4 d vs 3 d, p<0.001), and witnessed higher total charges (median $89,408 vs $55,559, p<0.001) and total cost (median $21,384 vs $17,279, p<0.001) than those in rural hospitals. Multivariate analyses revealed that patients in urban hospitals had higher odds of mortality (aOR 1.28, p=0.010), cardiogenic shock (aOR 1.55, p<0.001), cardiac arrest (aOR 1.31, p<0.001), requiring mechanical circulatory support (aOR 1.52, p<0.001), and acute kidney injury (aOR 1.24, p<0.001) compared to those at rural hospitals. Urban hospitals were also associated with lower odds of myocardial infarction (aOR 0.79, p<0.001) and major adverse cardiovascular and cerebrovascular events (aOR 0.85, p<0.001).

Conclusion:
Urban hospitals were associated with increased odds of mortality, cardiogenic shock, cardiac arrest, need for mechanical circulatory support, and acute kidney injury compared to rural hospitals. Despite ample resources at urban hospitals, differential baseline comorbidity burdens may have contributed to these differences thus underscoring the need to conduct prospective studies to better understand the factors responsible for these disparities.
Abstract 4147678: Distinct Echocardiographic Signatures Predict Mortality in Scleroderma Pulmonary Vascular Disease
Authors: Jani Vivek , Naranjo Mario , Knight Ethan , Mirson Leonid , Simpson Catherine , Hummers Laura , Wigley Fredrick , Shah Ami , Hsu Steven , Hassoun Paul , Mathai Stephen , Mukherjee Monica
Published: November 2024

Background:
Right ventricular (RV) contractile reserve is a main determinant of outcome in pulmonary arterial hypertension (PAH). PAH and RV maladaptation are common and portend a poor prognosis in the autoimmune disease systemic sclerosis (SSc). Clinical phenotyping of this subgroup of patients, however, remains imprecise. In the present study, we sought to identify whether unique speckle-tracking echocardiography (STE) derived phenotypic signatures predict outcomes in SSc.

Methods:
In a case-complete study design, 86 SSc patients with technically adequate echocardiograms referred for evaluation of possible PAH, right heart catheterization (RHC), serum laboratories, and pulmonary function testing (PFTs) were included for analysis. RV contractility was assessed using conventional and STE-derived RV free wall strain (RVFWS). Cluster analysis was used to identify sub-groups, which were sub-stratified to adjust for differences in RV afterload as indexed by pulmonary vascular resistance (PVR). A Mann-Whitney test was used for groups comparisons, and Kaplan-Meier survival analysis and Cox regression were used to test association with mortality.

Results:
Cluster analysis identified two distinct echocardiographic phenotypes in SSc, one with elevated pulmonary pressures (mean PA pressure 44±12 vs. 27±10, p<0.001), markedly elevated PVR (10±6 vs. 4±3 Wood units, p<0.001), and globally reduced RVFWS (-21±6 vs. -13±6 %, p<0.001) compared to the other. This group was associated with increased all-cause mortality (p=0.006). These differences may be driven by the increased PVR in one sub-group vs. another. To test whether RV dysfunction independent of PVR portends poor prognosis, we sub-stratified the cohort into one of three groups (
Figure
), one with relatively lower PVR (<5 WU) and preserved RVFWS, one with lower PVR but reduced RFWS, and one with markedly elevated PVR (>5 WU). This analysis found that patients with low PVR and reduced RVFWS had equally reduced survival (p=0.49) compared with those patients with elevated PVR.

Conclusion:
Echocardiographic phenotyping utilizing STE-derived RVFWS as a marker of contractile reserve revealed clinically relevant subgroups of RV dysfunction with diminished survival even after adjustment for RV afterload. These findings highlight the utility of STE in identifying SSc patients at greatest risk for poor clinical outcomes.
Abstract 4147722: Clinical impact of new severe tricuspid regurgitation following device lead extraction
Authors: Arunachalam Karikalan SUGANYA , O'Shea Michael , Vemulapalli Hema Srikanth , Mulpuru Siva , Killu Ammar , Siontis Konstantinos , Kowlgi Gurukripa , cha yong , Madhavan Malini , m ezzedine fatima , Desimone Christopher , Sugrue Alan , Padang Ratnasari , El Masry Hicham , Lee Justin , Deshmukh Abhishek
Published: November 2024

Introduction:
Tricuspid regurgitation (TR) is a common complication of right ventricle lead extraction (RVLE) in 5 to 10% of cases. This study aims to identify clinical outcomes such as predictors of heart failure hospitalization, need for tricuspid valve intervention, and death among patients with new severe TR after device lead removal (DLR).

Methods:
Patients who underwent DLR (pacemaker/ICD) between 3/1997 and 3/2024 were identified. Those who had an echocardiogram before and after RVLE with evidence of new severe TR were included. Cox univariable regression controlling for current age was used to assess association with death. Prentice Williams Peterson total time (PWPTT) Cox univariable regression was used to determine the rate of heart failure hospitalization up to three events per subject. Bivariable cox regression was used to control for ejection fraction for ICD and coil removal. Analysis was conducted using Stata IC16.

Results:
We identified 2,122 people who underwent RVLE, of whom 90 (4.24%) developed new severe TR and were included in the analysis. There were 68 hospitalizations among 38 people at a median of 2 years following lead extraction (IQR 0.57 to 4.5 years). The rate of hospitalization was 11.60 [9.14 to 14.71] per 100 person-years. Removal of an ICD was associated with increased hospitalization (HR 5.48 p<0.001) but not mortality (HR 1.21, p=0.707). Removal of a single coil ICD lead was associated with increased hospitalization rate (HR 3.01, p=0.031) but not mortality (HR =0.51, p=0.380). Removal of dual coil ICD lead was associated with more than a tenfold increase in hospitalization rate (HR 11.55, p=0.001) and four times the mortality rate (HR 4.05, p=0.031) (Figures 1&2). The presence of an abandoned (pacemaker/ICD) lead was associated with increased hospitalization (HR 5.75, p=0.004) and mortality (HR4.95, p=0.034). There was no change in hospitalization rate following tricuspid valve replacement (HR 1.33, p=0.716, n=18).

Conclusion:
Among people with new severe TR following DLR, the characteristics of the leads are strongly correlated with morbidity and mortality.
Abstract 4147779: Dynamin-Related Protein (DRP1) during Myocardial Ischemia-Reperfusion Injury: Culprit or innocent bystander?
Authors: kulek andrew , Przyklenk Karin
Published: November 2024

Background:
Dynamin-related protein (DRP1) is hailed as the “master regulator” of mitochondrial morphosis events and is understood to orchestrate fission and membrane permeabilization: events largely regarded as the apoptotic “point of no return”. Historically, DRP1 has been targeted through genetic downregulation and small-molecule inhibition, thereby mitigating apoptosis and lethal ischemia-reperfusion (IR).

Aim:
Our goal was to establish whether knockdown of cellular DRP1 has a protective effect in HL1 cardiomyocytes subjected to lethal IR.

Methods and Results:
To test this hypothesis, HL1 cells were transfected with siRNA against DRP1 (DRP1 KD group), scrambled siRNA, or vehicle and subjected to a standard IR insult or a time-matched normoxic period. Transfection with DRP1 siRNA achieved ~80% reduction in cellular DRP1. Transfected HL1 cells and matched controls underwent IR and viability analysis with the MTT assay. Our data show that in normoxic controls, DRP1 knockdown was associated with ~35% reduction in viability (Figure). In the IR group, IR produced a ~55% reduction in viability. However, contrary to our hypothesis, DRP1 knockdown modestly exacerbated rather than attenuated - cell death (Figure). To provide a mechanistic explanation for these findings, immunoblotting for markers of mitochondrial injury (i.e., cytochrome c, cleaved caspase 3, cleaved OPA1) were assessed following DRP1 knockdown. Knockdown of DRP1 associated with increases in cytosolic cytochrome c, cleaved caspase 3 and processing of OPA1.

Conclusion:
Prior studies have reported cardioprotection when DRP1 is either silenced or inhibited. Our data; however, suggests that DRP1 knockdown may promote mitochondrial injury pathways and worsen viability.
Abstract 4147784: Computational Fluid Dynamics is Key Predictors of Adverse Events in Single Ventricle Patients After the Fontan
Authors: Wei Zhenglun , Salargarna Fatemeh , Murawsky Jessica , Si Biao , Frechette Joshua , Carter Allen , Zou Jian , Yoganathan Ajit , Fogel Mark
Published: November 2024

Introduction:
Single ventricle patients following Fontan surgery may experience significant adverse outcomes. Hemodynamic metrics derived from image-based computational fluid dynamics (CFD) analysis could potentially serve as predictors.

Hypothesis:
CFD-based measures can prognosticate the consequences of Fontan surgery.

Methods:
This study randomly selected 217 Fontan patients who presented for cardiac magnetic resonance (CMR) from 2004-present obtaining anatomy and flows in the cavae and pulmonary arteries to obtain CFD. Hemodynamic metrics were indexed power loss (iPL, unitless) and resistance to flow in the Fontan connection (R
TCPC
, in WU). Recorded adverse events (AEs) included death, transplantation, cardiac arrest, admission to the cardiac intensive care unit, pleural effusion, catheterization, pacemaker implantation, protein-losing enteropathy, plastic bronchitis, liver fibrosis and cirrhosis, heart failure, and sustained ventricular tachycardia (VT). Independent two-sample Student's t-tests or Mann-Whitney tests were conducted depending on the normality of the data. Statistical significance was set at p < 0.05.

Results:
Age at initial CMR was 12.9 ± 8.2 years, with 37 patients undergoing a second CMR at 16.8 ± 8.1 years. Follow-up occurred 5.1 ± 2.6 years after the initial CMR. The number of patients who experienced an outcome is in Table 1. In the cross-sectional study (n = 217, Table 2), both iPL and R
TCPC
were significantly correlated with subsequent occurrence of AEs. Higher iPL was significantly associated with liver fibrosis (p = 0.027) and cirrhosis (p = 0.042) and showed a borderline statistical significance for death (p = 0.055). Higher R
TCPC
predicted liver cirrhosis (p = 0.043) and death (p = 0.045), with borderline significance for liver fibrosis (p = 0.058). The longitudinal study (n = 36, Table 3) demonstrated that changes in R
TCPC
predicted death (p = 0.029), while changes in iPL were borderline significant (p = 0.058). Additionally, changes in R
TCPC
were also significantly correlated with sustained VT.

Conclusion:
CFD-derived hemodynamics from CMR demonstrated promise as an important predictor of adverse events in single ventricle patients after Fontan. A larger prospective trial is warranted.
Abstract 4147789: The Efficacy and Safety of Cardiac Myosin Inhibitors Versus Placebo in Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: A Meta-Analysis of Randomized Controlled Trials
Authors: Ezenna Chidubem , Joseph Meghna , Murali Krishna Mrinal , Nelson Favour , Alugba Gabriel , Jenil Franco Ancy , Ramesh Prasana , Khawaja Uneza , Goldsweig Andrew
Published: November 2024

Introduction:
Obstructive hypertrophic cardiomyopathy (oHCM) is a genetic disorder characterized by asymmetric myocardial hypertrophy, which can obstruct left ventricular outflow. Recently, myosin inhibitors have emerged as a novel therapeutic targeting cardiac muscle hypercontractility.

Objective:
To assess the efficacy and safety of myosin inhibitors mavacamten and aficamten in patients with oHCM.

Methods:
We systematically searched PubMed, Scopus, and Cochrane Central databases for studies comparing mavacamten or aficamten to placebo in patients with symptomatic oHCM. Outcomes included improvement in peak oxygen consumption (pVO2) and NYHA function≥1 class (NYHA-FC), change in Kansas City Cardiomyopathy Questionnaire (KCCQ), peak left ventricular outflow tract gradient at rest (rLVOT) and with Valsalva maneuver (vLVOT) and treatment-emergent and serious adverse events. Random effects models generated risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs). Heterogeneity was assessed using I
2
statistics.

Results:
Search identified 5 randomized controlled trials including 767 patients (mavacamten 30.4%, aficamten 22.2%, placebo 47.4%) with mean follow-up of 22 weeks. Compared to placebo, myosin inhibitors were associated with improvement of ≥1 NYHA-FC (RR 2.33; 95%CI 1.92-2.82), rLVOT (MD -38.53; 95%CI [-46.06]-[-30.99]), vLVOT (MD -47.29; 95%CI [-58.03]-[-36.55]), pVO2 (MD 1.66; 95%CI 1.12-2.19), and KCCQ (MD 7.79; 95%CI 5.63-9.94) (Figure1). Other outcomes were similar with drug and placebo.

Conclusion:
Cardiac myosin inhibitors are an effective and safe short-term treatment for symptomatic oHCM.
Abstract 4147837: Task Effectiveness, Usability, and Acceptability of mHealth Technologies among Older Adults at Risk for Cardiovascular Disease: A Feasibility Study
Authors: Reyes Andrew Thomas , Candelaria Dion , Serafica Reimund , Hildebrand Janett , CACCIATA MARYSOL , Sta. Maria Axel , Lee Jung-Ah , Stromberg Anna , Evangelista Lorraine
Published: November 2024

Background:
New research shows the benefits of mobile health (mHealth) interventions for older adults. However, older adults adopt digital technology less than younger ones. Few technology acceptance theories focus on older adults. The research upon which these models are derived either employed a restricted sample size of older adults or completely excluded them from the study.

Purpose:
This study measures the task effectiveness, perceived usability, and acceptability of a mHealth intervention (i.e.,
Get FIT
+) consisting of a wearable activity tracker, access to the
MyFitnessPal
app, and personalized text messages to promote healthy behaviors in older adults.

Methods:
Participants used the
Get FIT
+ intervention for 12 weeks and engaged in monthly clinic visits with an advanced practice nurse (APRN) to monitor their progress. The monthly sessions instructed them to use the think-aloud process while doing specific tasks (e.g., using the app). Participants also completed the USABILITY Survey and provided feedback on the intervention's acceptability after the 12-week trial.

Results:
Thirty older adults (mean age 66.6 ± 5.9 years, 60% female, 60% married, 50% Asian, 37% White, and 13% Hispanic) participated in this sub-analysis. Participants were able to complete the assigned tasks efficiently. The usability satisfaction assessment suggests a high level of satisfaction. The participants responded positively to
Get FIT
+ and successfully incorporated it into their routines.

Conclusion:
Our findings show that
Get FIT
+ technologies, including smartphones, smartphone-based applications, and integrated sensors, are practical, usable, and acceptable for older adults at risk for cardiovascular disease. These scalable, low-cost technologies offer methods to monitor and promote a healthy lifestyle and enhance overall well-being.
Abstract 4147849: Extracellular Transcriptomics-driven Identification and Characterization of lncRNA LINC00989 in Heart Failure Progression
Authors: Gokulnath Priyanka , Spanos Michail , Sheng Quanhu , Singh Aarush , Chatterjee Emeli , Garcia Contreras Marta , Das Saumya
Published: November 2024

Introduction:
Heart failure (HF) poses a significant clinical challenge, necessitating a deeper understanding of its molecular mechanisms for effective therapeutic interventions. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cardiovascular diseases. However, their role in HF progression, particularly in human pericytes and association with cardiac remodeling, remains poorly understood.

Hypothesis:
We hypothesize that LINC00989, a novel lncRNA identified through plasma extracellular vesicle (EV) transcriptomics of ADHF patients, plays a significant role in human pericytes towards its profibrotic function and contributes to HF remodeling.

Methods:
We characterized LINC00989 expression in primary human pericytes and its response to stressors mimicking HF. Cellular and extracellular fractionation experiments were performed to examine LINC00989 localization and its association with EVs. Loss-of-function experiments were conducted using RNA anti-sense oligos, while gain-of-function experiments involved overexpression vectors. Further downstream interactors were characterized using RNA sequencing analysis. Profibrotic effects of LINC00989 were investigated using adoptive transfer model with induced pluripotent stem cell-derived cardiac fibroblasts.

Results:
Our findings demonstrate high expression of LINC00989 in primary human pericytes, with differential regulation under stress conditions. Loss-of-function experiments revealed alterations in epithelial-mesenchymal transition and angiogenesis markers, implicating LINC00989 in maintaining pericyte phenotype. Gain-of-function experiments supported its role in modulating pericyte morphology. Additionally, LINC00989 indicated a profibrotic role on cardiac fibroblasts.

Conclusion:
These findings underscore the significance of LINC00989 in human pericyte function and its potential as a therapeutic target in HF progression. Understanding its molecular mechanisms could lead to novel therapeutic interventions in heart failure. Further studies are needed to validate these findings and explore clinical implications.
Abstract 4147858: ECG correlates of chronic right ventricular pacing: QT interval predicts pacing-induced cardiomyopathy while QRS duration predicts cardiac resynchronization therapy response
Authors: Gupta Amulya , Shahab Ahmed , Harvey Christopher , Sheldon Seth , Reddy Madhu , Noheria Amit
Published: November 2024

Background:
Some patients with chronic right ventricular (RV) pacing develop pacing-induced cardiomyopathy (PICM) and benefit from upgrade to cardiac resynchronization therapy (CRT). However, there are no established ECG screening criteria for PICM.

Aim:
We sought to evaluate ECG correlates of (i) PICM and (ii) CRT response.

Methods:
We retrospectively identified all CRT upgrades (biventricular pacing) for PICM (LVEF <50%) at our center 2014-2018 and gauged CRT response (LVEF increase >5% on echocardiogram 3-12 months post CRT). Patients with ≥5 ECGs all demonstrating RV pacing over ≥2 years and all echocardiographic LVEF ≥50% served as controls. Root-mean-squared (3D) ECG was obtained from reconstructed orthogonal X, Y, Z leads. We used logistic regressions to predict PICM and CRT response from ECG intervals and voltage-time-integrals (VTI).

Results:
108 patients [74±11 years, 28% female, LVEF 29±8%, QRS duration (QRSd) 167±25 ms, QTc 515±39 ms] with CRT upgrade for PICM were compared to 186 controls (77±14 years, 53% female, LVEF 57±5%, QRSd 144±21 ms, QTc 473±33 ms). Discrimination of PICM was highest with QTc (AUC 0.80) followed by QRSd (0.77) and VTI
QRS-3D
(0.75,
Table 1, Figure 1
). QTc >480 ms detected PICM with sensitivity 84% and specificity 74%. With CRT upgrade
,
LVEF improved by 14±11%. CRT response (ΔLVEF >5%) occurred in 77/108 (71%). Lack of CRT response was best predicted by QRSd (AUC 0.65) followed by ΔVTI
QRS-3D
(0.61,
Table 2
). Lack of CRT response was noted in 52% with QRSd >180 ms, while 78% with QRS duration ≤180 ms showed CRT response.

Conclusions:
In patients with chronic RV pacing, QTc >480 ms identifies those susceptible to PICM, and QRSd >180 ms identifies those who may not respond to CRT.
Abstract 4147874: Plasmalemma Vesicle-Associated Protein (PLVAP) regulates Cardiac Endothelial Permeability is ARNT-dependent
Authors: Ullah Md Karim , Wu Qiong , humayun zainab , Jiang Jing , Rajasekaran Snekha , Kim Ha Ram , Fang Yun , Wu Rongxue Rosie
Published: November 2024

Background:
Disruption of microvascular endothelial integrity significantly contributes to ischemic cardiovascular injury. PLVAP is an endothelial-specific integral membrane glycoprotein localized to caveolae and fenestrae, predominantly expressed in cardiac microvascular endothelial cells (CMVECs). The precise role of PLVAP and its regulatory mechanisms remain unclear. We hypothesize that Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) modulates PLVAP to regulate cardiac barrier function.

Methods and Results:
We utilized primary CMVECs isolated from inducible endothelial-specific ARNT knockout (KO) mouse hearts and human CMVECs treated with siRNA. ARNT deletion resulted in reduced PLVAP expression at both protein and mRNA levels (P < 0.0001). Chromatin immunoprecipitation followed by qPCR (ChIP-qPCR) confirmed that ARNT binds to the PLVAP promoter region, indicating transcriptional regulation of PLVAP by ARNT. Promoter assays further demonstrated that ARNT regulates PLVAP expression (P < 0.0001). Immunofluorescence staining with wheat germ agglutinin (WGA) revealed a significant reduction in the glycocalyx layer in PLVAP-deleted human microvascular endothelial cells, alongside decreased expression of endothelial junctional proteins VE-Cadherin and Occludin. Conversely, activating ARNT/HIF1α heterodimers using a prolyl-4 hydroxylase inhibitor (DMOG) or overexpressing ARNT restored the endothelial glycocalyx, permeability, and VE-Cadherin expression in LPS-stimulated cells. Furthermore, ARNT activation increased the size of plasmalemma vesicle pores and heightened endothelial permeability in human primary endothelial cells.

Conclusions:
This study highlights the vital role of the endothelial ARNT in regulating PLVAP which controls vascular permeability. These findings provide insights into the molecular mechanisms of endothelial permeability and identify potential therapeutic targets for treating vascular and cardiac complications.