bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13990: Tightly Connected Provider Networks Are Associated With Lower Spending for Patients Undergoing Left Ventricular Assist Device Implantation
Authors: Kim Dennie , Funk Russell , Hou Hechuan , Airhart Austin , Nassar Khalil , Pagani Francis D , Zhang Min , Chandanabhumma Paul , Aaronson Keith D , Chenoweth Carol , Hider Ahmad , Cabrera Lourdes , Likosky Donald S ,   behalf of the Michigan Congestive Heart Failure Investigators
Published: April 2024

Introduction:
Patients receiving a durable left ventricular assist device (LVAD) implant for advanced heart failure require multidisciplinary care but integration of care delivery may vary among provider groups. Prior studies found that greater provider network connectivity may be associated with more integrated care and better clinical outcomes.

Hypothesis:
Greater connectedness in provider networks is associated with lower LVAD payments.

Methods:
Drawing on social network theory, a measure of connectedness was developed based on the number of shared patients among providers (e.g. primary care physicians, cardiologists, surgeons) caring for 4,985 Medicare beneficiaries, starting 180 days prior to LVAD admission until 180 days post-discharge, from July 2009-April 2017. Connectedness was measured as average network path length, with shorter path lengths indicating more connected networks. Total payments were captured from admission to 180 days post-discharge. Multivariable regression was used to analyze the relationship between connectedness and LVAD payments.

Results:
The patient cohort was 81% male, 73% white, 11% Intermacs Profile 1 with a mean age of 63.1 years (SD 11.1). The median path length (IQR) for a provider network was 1.7 (1.6, 1.8) and median (IQR) payments from admission to 180 days post-discharge was $162,774 ($151,279, $202,932). Median (IQR) payments at the lower, middle, and upper terciles of connectedness were $162,249 ($150,543, $198,709), $162,577 ($151,424, $199,471), and $163,922 ($152,263, $212,072), respectively. After adjusting for center, patient demographics, and clinical factors, greater connectedness was associated with lower payments (β=-22097.88, p<0.01), Figure.

Conclusions:
Greater provider network connectedness is associated with lower payments for Medicare beneficiaries receiving durable LVAD implants. Interventions to improve network connectedness may improve the value of care in this population.
Abstract 13998: Predicting Atrial and Ventricular Tachyarrhythmias by Monitoring Intra-Thoracic Impedance, an Updated Meta-Analysis
Authors: Alzu'bi Hossam , Al-abdouh Ahmad , Haq Ikram-Ul , AbuRmilah Anan , Deshmukh Abhishek
Published: April 2024

Background:
Many cardiac implantable devices have the capability of monitoring the volume status in patients with heart failure by tracking the intra-thoracic impedance changes over time measured by OptiVol fluid index.

Objective:
The aim of this study is to evaluate the association between the intra-thoracic impedance measured by OptiVol fluid index and the onset of tachyarrhythmias.

Methods:
We searched Medline and EMBASE databases through January 2021 looking for studies evaluating intra-thoracic impedance measured by OptiVol with either ventricular tachycardia/ventricular fibrillation (VT/VF) or atrial tachycardia/atrial fibrillation (AT/AF). After extracting the data from each study, we calculated the odds ratio with 95% confidence intervals using RevMan 5 software.

Results:
Ten studies met our inclusion criteria with a total of 118,504 patients were included in our analysis. Seven studies measured VT/VF included 94,816 patients and 5 studies measured AT/AF included 23,688 patients. Two studies measured both AT/AF and VT/VF. The odds ratio for developing VT/VF with OptiVol fluid index crossing a threshold of 60 Ω-days was 1.55 (95% CI 1.35, 1.78) (P<0.00001) and for developing AT/AF was 1.79 (95% CI 1.43, 2.24) (P<0.00001) {Figure1}

Conclusion:
The decrease in intra-thoracic impedance measured by OptiVol fluid index threshold crossing of 60 Ω-days is associated with higher risk for developing new onset AT/AF and VT/VF.

Key Words:
intra-thoracic impedance; OptiVol; tachyarrhythmia

Figure1:
Forest Plot for risk of developing VT/VF

Figure:
Forest Plot for risk of developing AT/AF
Abstract 14103: Loss of Bone Morphogenetic Protein (BMP) 9 Activity Reduces Survival and Increases Collagen Turnover via Enhanced Matrix Metalloproteinase Activity After Acute Myocardial Infarction
Authors: Bhave Shreyas , Esposito Michele , Swain Lija , QIAO Xiaoying , Martin Gregory , Everett Kay , Kapur Navin K
Published: April 2024

Introduction:
Acute myocardial infarction (AMI) is a major cause of heart failure and mortality. The extracellular matrix plays a central role in post-infarct remodeling. We recently reported that BMP9 negatively regulates cardiac fibrosis in heart failure. A functional role for BMP9 in post-infarct remodeling remains poorly defined. We hypothesize that BMP9 signaling via activin like kinase 1 (ALK1) promotes survival after AMI by negatively regulating fibrosis and limiting matrix metalloproteinase (MMP) activity.

Methods:
AMI was induced by left coronary artery ligation in wild type (WT), BMP9-/- and ALK-/+ mice. After 14 days, LV function was assessed using conductance catheter and myocardial BMP9 signaling pathways were studied. In vitro siRNA mediated protein knockdown in human atrial fibroblasts (AtFB) further tested this signaling pathway.

Results:
BMP9-/- and ALK-/+ mice had significantly reduced survival after AMI compared to WT (p=0.04 and 0.008 respectively) and was associated with an increased incidence of cardiac rupture. LV ejection fraction decreased significantly among BMP9-/- and ALK1+/- survivors compared to sham (p<0.01 for both). pSMAD3 was increased and pSMAD1 decreased in both BMP9-/- and ALK1-/+ mice after AMI. Reduced pSMAD1 expression was directly associated with increased type 1 collagen levels in BMP9-/- (R
2
=0.48, p=0.02) and ALK1-/+ (R
2
=0.42, p=0.01) mice compared to WT. LV protein levels of endoglin increased significantly in both BMP9-/- and ALK+/- compared to WT sham (p<0.01 for both) after AMI. LV levels and activity of MMP9 were increased in BMP9-/-, but not in ALK1+/-, compared to WT after AMI (p=0.02 and 0.8 respectively). Circulating biomarkers of collagen degradation:synthesis (ICTP:PINP ratio) increased significantly (p=0.02) in BMP9-/- compared to WT after AMI. BMP9 but not ALK1 knockdown in AtFBs increased expression and activity of MMP9 (p=0.01 and 0.3 respectively).

Conclusions:
These findings identify a novel functional role for BMP9 and ALK1 as determinants of post-infarct survival and cardiac remodeling and further suggest that loss of BMP9-ALK1 signaling increases collagen degradation and turnover. BMP9/ALK1 signaling may be a novel target of therapy for post-infarct remodeling and survival.
Abstract 14121: Trends In Awareness, Use Of Medication, And Blood Pressure Control By Race And Ethnicity Among U.S. Adults With Hypertension: A 20-year National Health And Nutrition Examination Survey Analysis, 1999-2018
Authors: Lu Yuan , Liu Yuntian , Dhingra Lovedeep , Massey Daisy , Caraballo Cesar , Mahajan Shiwani , Herrin Jeph , Krumholz Harlan M
Published: April 2024

Introduction:
Black and Hispanic adults have poorer hypertension control compared with White adults in the US. Less is known about the country’s progress in eliminating disparities in awareness and treatment of hypertension and whether these differences explain the difference in hypertension control.

Methods:
We assessed 20-year trends in racial/ethnic differences in awareness, use of medication, and whether these differences help explain racial/ethnic difference in blood pressure (BP) control in the US population, using data from 59,204 hypertensive adults enrolled in the National Health and Nutrition Examination Survey (1999-2018).

Results:
For all 3 racial groups (White, Black, and Hispanic), hypertension awareness, treatment, and control rates increased between 1999-2013, and then declined between 2014-2018. Although Black adults had a lower BP control rate (odds ratio: 0.77 [0.70-0.85]) compared with White adults, they had a higher awareness rate (1.30 [1.13-1.46]), a similar overall treatment rate (1.07 [0.94-1.19]) and received more intensive antihypertensive therapy (OR for combination therapy 1.32 [1.19-1.45]). Hispanic adults had a significantly lower BP control rate (0.68 [0.59-0.77]), awareness rate (0.76 [0.65-0.85]), overall treatment rate (0.65 [0.55-0.74]) and received less intensive therapy compared with Black and White adults. From 1999-2018, the racial/ethnic differences in awareness, treatment, and BP control persisted and were more pronounced among younger (<60 years of age), male, and lower income adults. Lower awareness and treatment were associated with lower BP control in Hispanics, but not in Blacks.

Conclusions:
Although Blacks had higher level of awareness and received more intensive antihypertensive therapy, Hispanics were less aware and treated than White. Racial/ethnic differences in awareness and treatment partially explain difference in hypertension control for Hispanics, but not for Blacks.
Abstract 14124: Long-term Cardiovascular Mortality Disparities By Race In The Us Adult Population
Authors: Banerjee Srikanta , Harvey David , Banerjee Karen , Schwab Michael
Published: April 2024

Cardiovascular disease remains the leading cause of mortality and disproportionately affects vulnerable populations. Among disparities in overall mortality, Black Americans experience higher mortality rates than White Americans. However, it is unknown, if the same disparities persist after long-term follow-up. In this study, we assessed the hypothesis that Non-Hispanic Black Americans experience higher 10-year cardiovascular disease (CVD) mortality follow-up than Non-Hispanic White Americans.

We analyzed data on adults (≥ 20 years) from the 1999-2010 National Health and Nutrition Examination Survey, with mortality data obtained through 2015. The causes of death for adults (N=4037) were defined using the International Classification of Disease coding (ICD-10). Complex Samples Cox regression was used to assess if diabetes status modified the relationship between race and CVD-mortality.

Out of the respondents (N=4037), 17.7% of Non-Hispanic Blacks individuals died from CVD versus 16.4% among Non-Hispanic White counterparts. During the 11-year follow-up, the hazard ratio (HR) for CVD-mortality among Non-Hispanic Black Adults, with adjustment for age and gender only, was 1.36; 95% confidence interval [CI: 1.11, 1.67]. Over the age of 20, there is higher CVD-mortality in Non-Hispanic Black men (HR, 1.15; 95% CI, 0.91–2.05, p > .05) and women (HR, 2.50; 95% CI, 1.56–3.99, p < .01) than in their White counterparts even after controlling for medical (obesity, CVD, diabetes) and demographic (education, age, food insecurity level, and poverty level) variables.

In conclusion, Black Americans experience higher probability of death from cardiovascular disease in 10-year follow-up than other races. Due to the chronicity of CVD, disparities are compounded over a long period of time. The observed ethnic disparities in treatment and control, with the relative deficits observed in Black Americans, are potentially due to ethnic differences in healthcare-seeking behaviors and access to care. Policy considerations should address how to improve equitable screening and prevention, as it pertains to race.
Abstract 14142: Life After Left Ventricular Assist Device (LVAD) Implant: A Qualitative Perspective Through Online Focus Groups Of LVAD Caregivers
Authors: Xu Ashley J , Li Mengchi , Byiringiro Samuel , Wenzel Jennifer , Dennison Cheryl
Published: April 2024

Introduction:
The caregivers’ role is integral for individuals with a left ventricular assist device (LVAD). Caregivers from other chronic diseases (heart failure, stroke, and cancer) experience uncertainty related to caring for their loved ones. However, there is a lack of literature in the LVAD caregiver population. This study explored factors related to uncertainty in LVAD caregivers.

Methods:
This qualitative study included utilization of synchronous online focus groups through a secure platform. Caregivers (N=20) were recruited through three Facebook LVAD support groups. Participants were assigned based on availability to one of five, 60-min, private, online focus group sessions. Topics explored were guided by the Uncertainty in Illness Theory. NVIVO 12 was used to analyze content into codes and common themes.

Results:
Focus group results yielded 5 overarching themes: 1) Caregiver perceived positive experiences can lead to hopefulness and a sense of normalcy. 2) Caregiver perceived negative experiences have impact on caregiver health and everyday activities. 3) Coping strategies to the changes (whether perceived negative or positive) are crucial in improving overall experience and regain “sense of control”. 4) Adjusting and adapting can improve quality of life. 5) Caregiver needs are multidimensional and strategies that improving coping are needed to enhance experience.

Conclusions:
The study found caregivers experience coexistence of ambivalent emotions from positive to negative. They utilize different coping strategies to cope with the changes and uncertainties in the everyday life. However, they still encounter many challenges and have many unmet needs.Access to resources like financial assistance, monitoring of mental health and referral to a professional, constant exchange of information (receiving or sharing) from the centers and keeping caregivers/patient informed and engaged could all enhance the caregiver experience.
Abstract 14191: New Approaches to Factual and Counterfactual Risk Prediction for Cardiovascular Disease Using the Parametric G-formula
Authors: Boyer Christopher B , Danaei Goodarz
Published: April 2024

Introduction:
Over the last few decades, clinical prediction models of the risk of cardiovascular disease have proliferated and are now used extensively in research and clinical care. However, most models have several limitations: (1) they often use only the baseline examination cycle despite the fact that the underlying data sources often include longitudinal assessments of risk factors over time, (2) they make predictions under the "natural course" for the population from which they were derived without making explicit how risk factors varied over time, and (3) they are not appropriate for predictions under alternative counterfactual scenarios such as if an individual were to initiate treatment or adopt healthy lifestyle changes. In this study, we consider an alternative approach based on the parametric g-formula which resolves these limitations.

Methods:
We compare a g-formula-based model to standard approaches to prediction modeling via Monte Carlo simulation as well as in empirical data. For the latter, we use data from 14,222 longitudinal assessments of 2,771 participants in the Framingham Offspring Study (FOS) to predict 10-year risk of ASCVD. Model discrimination and calibration are assessed via C statistic and calibration slope. We also investigate improvements in risk estimates from our g-formula model as compared to those from the Pooled Cohort Equations (PCE) using the integrated discrimination index and net reclassification index.

Results:
In simulations, the g-formula model performs better than standard approaches when longitudinal observations are added and makes correct counterfactual predictions when assumptions are met. When applied to FOS data, the g-formula model had better discrimination (C statistic, 0.77 vs. 0.73) and better calibration (slope, 1.07 vs. 0.83) than the PCE. Improvements in the net re-classification index at the 7.5% risk threshold (0.14; 95% CI: 0.05 - 0.26) as well as the integrated discrimination index (2.6%; 95% CI: 1.5% - 3.7%) were significant, suggesting the g-formula better classifies those at increased risk of ASCVD.

Conclusion:
A longitudinal model based on the g-formula could better use available data from cohort studies and provides a principled framework for predicting risk under interventions.
Abstract 14211: In-Hospital Mortality and Length of Stay Among Patients Hospitalized With Acute Heart Failure and Vitamin D Deficiency: A Study From National Inpatient Sample 2016-2017
Authors: Adhikari Govinda , Santiago-Rivera Olga , Baral Nischit , Rauniyar Rohit , Khan Mahin , Mallikethi Lepakshi Reddy Sagar , Sud Parul , Kesari Kavitha , Changezi Hameem , Hassan Mustafa
Published: April 2024

Introduction:
Vitamin D deficiency (VDD) is highly prevalent in patients with Congestive Heart Failure (CHF) and associated with adverse clinical outcomes. VDD is thought to over-activate neurohormonal and inflammatory responses leading to left ventricular dysfunction.

Hypothesis:
VDD status is associated with increased in-hospital mortality rate and length of stay (LOS) in patients with acute heart failure.

Methods:
We used the National Inpatient Sample (NIS) data from 2016-2017 to examine a possible association between VDD and in-hospital mortality or LOS among patients hospitalized with acute heart failure (AHF). We included patients 18 years or older with a primary diagnosis of AHF. Other covariates of interest included sex, age, race, insurance, income quartile by zip code, comorbidities, hospital location, and size. We used the Charlson Comorbidity Index (CCI) categories to account for comorbidities. Bivariate analyses included Chi-square and Fisher's exact test with categorical variables and mean and median test for LOS to examine possible group differences among patients with AHF. We ran unadjusted and adjusted regression models to test the study hypothesis.

Results:
We identified a total of 177,811 acute heart failure discharges. Two percent (n= 3542) had VDD. The mean age in a VDD group was 72.8 ±14.06 years while in a non-VDD group was 71.5 years±14.49 (p < 0.001). Among VDD patients, 56.06% were females (p < 0.001); 66.70% were White, 21.70% were black, 6.61% were Hispanic (p < 0.001); 18.66% were in Northeast, 30% in Mid-west, 33.8% in South and 17.5% in West hospital region (p < 0.001). There was a higher proportion of Charlson Comorbidity index of three or more in VDD compared to non-VDD (80.12% vs. 69.41%; p < 0.001) group. VDD status was associated with 31.5% decrease in odds of in-hospital mortality compared to non-VDD status (Adjusted Odds Ratio 0.68, 95% C.I. 0.54- 0.87, p = 0.002). However, there was a small but statistically significant increase in length of stay (β = 0.95, linearized S.E. ± 0.18, 95% C.I. 0.06-0.13, p-value < 0.001) in patients with VDD compared to non-VDD.

Conclusions:
VDD status is associated with statistically significant increased LOS, but lower in-hospital mortality in patients hospitalized with AHF.
Abstract 14217: Myofibroblasts Enhance the Intrinsic Sinus Rhythm at Low Cell-Cell Coupling
Authors: Kim Tae , Fan Jinqi , Chung Mingee , Cho Hee C
Published: April 2024

Heart rhythm is initiated by the sinoatrial node (SAN). Compared to the chamber myocardium, the healthy SAN exhibits an exceedingly high content of fibroblasts (FBs). Developmental, aging and pathophysiological cues can activate FBs to myofibroblasts (MFBs) which exhibit depolarized membrane potential and stronger electrotonic coupling compared to FBs. We hypothesized that MFBs, at a low content, can paradoxically increase the pacing frequency of pacemaker cells (PMs) by contributing to the spontaneous depolarization slope.Monolayers and scaffold-free 3D spheroids of TBX18-induced PMs (iPMs) were generated as in vitro models of SAN by somatic gene transfer of TBX18 to neonatal rat cardiomyocytes. Retrograde-perfused, adult rat heart was employed to study intact SAN ex vivo. In silico modeling was performed to simulate pacing frequencies of PMs coupled to MFBs in 2D and 3D pacemaker tissues. Upon reducing electrotonic coupling with carbenoxolone (CBX, 5μM), pacing frequency of iPM monolayers either increased from 66 ± 51 to 168 ± 92 bpm (n=4/13) or decreased from 125 ± 47 to 98 ± 28 bpm (n=9/13). GFP-transduced control NRVM monolayers (n=8) showed only occasional activity, which was not affected by CBX treatment (|ΔBR| = 57 ± 69 in iPM monolayers vs. 11± 11 bpm in control, GFP monolayers, p<0.05). In culture, FBs are known to undergo spontaneous activation to MFBs via TGFβ signaling. Treatment of iPM spheroids with a TGFβ inhibitor (SB431542, 10μM) slowed their automaticity to 124 ± 89 bpm compared to 214 ± 18 bpm in untreated iPM spheroids. Sinus rhythm of the rat heart ex vivo increased upon CBX treatment from 199 ± 64 to 242 ± 80 bpm (n=3, p=0.07). Immunostaining confirmed presence of αSMA+ MFBs in both iPMs and the SAN. Computational study demonstrated that pacing frequencies of 2D and 3D PMs rose and fell with increasing gap junction conductance when coupled to MFBs (Vrest = -25 mV, g = 0 to 4.0 nS) but not to FBs (Vrest = -50 mV, g = 0 to 0.4 nS). Dynamic range of cardiac pacing was optimal when the ratio of MFB to PM was no more than one.Our data demonstrate that MFBs positively contribute to the pacing frequency and the safety factor of the sinus rhythm. We identify fibroblast activation state as a potential target to rejuvenate heart rhythm under aging and pathological conditions.
Abstract 14219: White Cell Inflammatory Biomarkers in Women With Myocardial Infarction With Non-Obstructive Coronary Artery Disease (MINOCA): Findings From the American Heart Association Go Red for Women Strategically Focused Research Network
Authors: Berger Jeffrey S , Myndzar Khrystyna , Barrett Tessa A , Xia Yuhe , Smilowitz Nathaniel , Hausvater Anais , Bangalore Sripal , Razzouk Louai , Shah Binita , Spruill Tanya , Hochman Judith S , Reynolds Harmony
Published: April 2024

Introduction:
Myocardial infarction (MI) with non-obstructive coronary artery disease (MINOCA) occurs in 5-20% of women with MI. Underlying mechanisms of MINOCA are incompletely understood. Complete blood count (CBC) quantifies circulating cell types and can shed mechanistic insight into disease pathogenesis..

Methods:
Peripheral blood was collected from women with MINOCA (n = 50; median 64 years [IQR 51-69]) and MI with coronary artery disease (MI-CAD; n = 71; 61 years [55-70]). Controls were women referred for elective cardiac catheterization
found not to have
obstructive CAD (n = 65; 62 years [57-69]). Blood was analyzed at the time of catheterization and in a subset of participants after 2 months. Associations between CBC parameters and MI subtype were estimated by multivariable logistic regression.

Results:
Overall, women with MI had higher WBC (p=0.008), monocyte counts (p<0.001), neutrophil counts (p=0.001), monocyte:lymphocyte ratio (p<0.001), and neutrophil:lymphocyte ratio (p<0.001) than controls. No significant difference was noted for lymphocyte count, hemoglobin, platelet count and platelet size. When comparing MINOCA versus MI-CAD, there was no significant difference in age, race/ethnicity, diabetes, hypertension, and peak troponin. Women with MINOCA had lower WBC and neutrophil counts than MI-CAD at the time of MI. Compared to controls, women with MINOCA had higher monocyte counts, monocyte:lymphocyte ratio, and neutrophil:lymphocyte ratio. After adjustment for demographics, hypertension, hyperlipidemia, and diabetes, only monocyte count (β 0.22, p=0.04) and monocyte:lymphocyte ratio (β 0.32, p=0.005) were significantly associated with MINOCA (versus controls). Among 13 women with MI-CAD and 15 with MINOCA who had blood analyzed 2 months post their MI, monocyte count and monocyte:lymphocyte ratio decreased in the MI-CAD group, but did not decrease in the MINOCA group.

Controls:
In contrast leukocytosis across all white cell types in MI-CAD, women with MINOCA have a higher monocyte count and monocyte:lymphocyte ratio than controls. These parameters remained elevated over time in a pattern different from MI-CAD, suggesting a mechanistic role of monocytes in the pathogenesis of MINOCA.
Abstract 14244: SCD-HeFT Reanalyzed - A Need for Multimorbidity Risk-Stratified Trial Evaluations for Clinical Interventions
Authors: Hegwood Emma , Naccarelli Gerald , Schaefer Eric , Foy Andrew
Published: April 2024

Introduction:
Patients with multiple chronic conditions (i.e., multimorbidity) are under-represented in clinical trials. This represents a challenge to the external validity of clinical trials since multimorbidity may associate with treatment effect heterogeneity (HTE). In this analysis, we sought to determine the distribution of multimorbidity scores in patients enrolled in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) and looked for an association between such scores and HTE for the outcome of all-cause mortality.

Methods:
A modified version of the Charlson Comorbidity Index (mCCI) was created using enrollment data. For the subgroup analysis, we fit a Cox model that included comorbidity index, randomized group, and their interaction. The interaction term allows the effect of randomized group to differ by level of comorbidity index, and is the primary effect of interest. The comorbidity index was modeled using quartiles. Following the same analysis framework as the original manuscript Amiodarone or ICD was compared to placebo in separate models.

Results:
The majority of patients had a mCCI score ≤ 5 (75.4%) and mortality risk was strongly associated with increased score. Interaction testing across subgroups suggested HTE for Amiodarone (
p = 0.07
) or ICD (
p = 0.08
) vs placebo as scores increased. For Amiodarone, the Q1 and Q4 HRs were 0.78 (0.43-1.39) and 1.50 (1.03-2.18), respectively. For ICD, the Q1 and Q4 HRs were 0.42 (0.20-0.84) and 0.99 (0.67-1.47), respectively (see Figure).

Conclusions:
Increasing multimorbidity may be associated with HTE for all-cause mortality when comparing Amiodarone and ICD to placebo in the SCD-HeFT trial. Our results highlight the importance of enrolling patients with advanced multimorbidity when considering interventions. As statistical power remains challenging in trial sub analysis, consideration should be given to performing separate trials for patients with more advanced multimorbidity.
Abstract 14257: Ribosome-Profiling Reveals Translational Control of SND1 as a Determinant of Endothelial Homeostasis in a hiPSC Model of Sunitinib-Induced Vascular Dysfunction
Authors: Han Zhenbo , Jousma Jordan , Amiri Mehdi , Tabatabaei Negar , Nukala Sarath B , Kwon Youjeong , Yan Gege , Tahmasebi Soroush , Lee Won Hee H , Ong Sang-Ging
Published: April 2024

Introduction:
The advent of tyrosine kinase inhibitors in cancer therapies has contributed towards the lowered mortality rate from cancer deaths; however, resulting vascular toxicity from such drugs increases the risk for fatal heart disease in cancer survivors. Thus, a better understanding of the mechanisms related to adverse cardiovascular effects is needed to improve mortality rates in cancer survivors.

Hypothesis:
The objective of this study is to identify previously unrecognized molecular targets that are regulated at a translational level which may contribute to sunitinib-induced vascular toxicity.

Methods and Results:
A human induced pluripotent stem cell-derived endothelial cells (hiPSC-EC) model of sunitinib-induced vascular dysfunction was established. Ribosome profiling which allows the selective sequencing of translated RNA regions identified Staphylococcal nuclease domain-containing protein 1 (SND1) as a translationally-repressed gene caused by sunitinib exposure. Mechanistically, we identified that sunitinib repressed SND1 by inhibiting mTOR which in turn dephosphorylates 4E-BP. Double-knockdown of 4E-BP1/2 reversed sunitinib-induced repression of SND1. Loss-of-function studies revealed that SND1 inhibition led to endothelial dysfunction as measured by reduced cell viability, impaired angiogenic capability, and reduced wound healing; effects which were blunted in reciprocal SND1 gain-of-function studies in the presence of sunitinib treatment. Furthermore, our results revealed that SND1 transcriptionally regulates UBC13, an E2-conjugating enzyme that mediates K63-linked ubiquitination. Pharmacological inhibition of UBC13 also led to endothelial dysfunction similar to the detrimental effects of sunitinib or SND1 inhibition.

Conclusions:
Our study demonstrates that translational control of SND1 which acts through UBC13 is a previously unidentified mechanism that can potentially be manipulated for therapeutic benefits to reduce sunitinib-induced vascular toxicity.
Abstract 14269: The Association of Treadmill Exercise Test-Derived VO
2
Max and Symptomology in Athletes and Non-Athletes With Hypertrophic Cardiomyopathy
Authors: Garmany Ramin , Bos J. Martijn , Newman Darrell B , Geske Jeffrey B , Allison Thomas G , Ommen Steve R , Ackerman Michael J
Published: April 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death in the young and especially in young athletes. The treadmill exercise test (TEST) has an important role in the functional assessment of patients with HCM. Herein, TEST-derived peak oxygen uptake (VO2 max) is a proxy for cardiopulmonary fitness. However, the correlation between symptoms and VO2 - especially in active young patients with HCM - is unclear.

Objective:
To explore the relationship between TEST-derived VO2 and symptomology in athletes and non-athletes with HCM.

Methods:
Overall, 91 patients (40% female) with HCM and a TEST with VO
2
data were included in this case-control study. Data were abstracted from the electronic health record using the first TEST performed at Mayo Clinic. Patients were defined as an athlete if they participated in an organized, competitive sport.

Results:
Overall, 60 HCM patients (33% female) were categorized as an athlete. HCM athletes were younger (17 vs. 27 years; p<0.0001) and less likely to be symptomatic at the time of their TEST (OR=0.24; p=0.01). Additionally, athletes had a higher VO2 max (86% vs. 68% of predicted; p<0.0001) and reached higher exercise times (93% vs 76% of predicted; p<0.0001) compared to the non-athletes with HCM. When comparing symptomatic (n = 18) to asymptomatic patients (n = 73), symptomatic patients had i) a reduced exercise time (68% vs. 92% of predicted; p=0.002) and ii) lower VO2 max (62% vs 84% of predicted; p<0.001). Finally, among the 27 patients (30%) with a VO
2
max < 70% predicted (n=27), they i) more likely had a history of cardiac arrest (4 vs 0; p=0.006) and ii) were more likely to be symptomatic (OR=7.7; p< 0.0001) than those with VO2 ≥ 70% of predicted (n=64). Importantly, however, 15/27 (56%) patients (8 athletes/7 non-athletes) with a VO2 max < 70% were asymptomatic.

Conclusions:
Reduced exercise capacity is common in athletes with HCM and does not correlate with symptom status. However, if the TEST-derived VO2 max is < 70%, treatment intensification may be necessary as it may portend an adverse outcome both arrhythmically and mechanically.
Abstract 14277: Diagnostic Accuracy of the 12-lead Electrocardiogram in the First 48 Hours of Life in Neonates From a Parent With Genotype Positive Long QT Syndrome
Authors: Tobert Kathryn E , Perez Yalile , Bos Martijn , Ackerman Michael J
Published: April 2024

Introduction:
Long QT syndrome (LQTS) is an autosomal dominant disorder characterized by a prolonged QT interval on a 12-lead electrocardiogram (ECG). Cascade genetic testing for LQTS is standard of care, including in infants, but takes 2-4 weeks for return of results. For newborns of parent with confirmed LQTS, the ECG is obtained after birth as an initial assessment, but QTc values during the immediate newborn period may be misleading. Thus, our objective was to determine the ECG’s diagnostic accuracy in the first 48 hours of life for neonates born to a parent with LQTS.

Methods:
We performed a retrospective review of the electronic medical records of neonates born to a parent with ≥ 1 pathogenic variant in a LQTS-causative gene for which at least 1 ECG in the first 48 hours of life was obtained. Clinical data was collected on all neonates with focus on the 12-lead ECG, family history, and genetic testing results. The sensitivity and specificity of the diagnostic ECG were calculated using QTc thresholds of 440, 460, and 470 ms.

Results:
Overall, 70 infants (35 [50%] females) met inclusion criteria and the mean QTc on the first ECG was 484 ± 61 ms. Following genetic testing, a LQTS-causing variant was identified in 46 infants (66%), including 22 (48%) with LQT1 (
KCNQ1
), 12 (26%) with LQT2 (
KCNH2
), and 8 (17%) with LQT3 (
SCN5A
). Mean QTc in the first 48 hours of life for neonates that ultimately were genotype-positive was 502 ± 59 ms compared to 451 ± 50 ms (p < 0.001) for genotype-negative neonates. When using a recommended threshold QTc of ≥ 440 ms, 6/46 genotype-positive neonates (13%) were missed (underdiagnosed) and 13/24 genotype-negative neonates (54%) were overdiagnosed (sensitivity: 87%, specificity: 45%). At a QTc threshold ≥ 460 ms, 15 (21%) were classified erroneously (sensitivity: 85%, specificity: 67%) while at a threshold of ≥ 470 ms, 18 (26%) were misclassified (sensitivity: 76%, specificity: 71%).

Conclusions:
Although a baseline ECG should still be obtained before a newborn’s dismissal, reliance solely on the QTc for diagnosing LQTS and initiating therapy will result in an unacceptable number of misclassifications. Thus, genetic testing must be initiated prior to the baby’s discharge and proper anticipatory guidance is vital while awaiting genetic test results.
Abstract 14293: Automated Arrhythmia Detection in HiPSC-Derived Cardiac Cell Sheet Models for Drug Testing and Disease Modeling
Authors: Landesberg Michal , Huber Irit , Gepstein Amira , Arbel Gil , Gepstein Lior
Published: April 2024

Introduction:
The use of human-induced pluripotent stem cells (hiPSC) derived cardiomyocytes may bring a unique value for drug testing and disease modeling applications. In this project, we developed an automatic and robust arrhythmia detection tool that enables recognition of early-after-depolarizations (EADs) and reentrant activity (spiral waves) in hiPSC-derived cardiac tissue models.

Methods and Results:
hiPSCs were differentiated into cardiomyocytes, seeded as large-scale hiPSC-derived cardiac cell-sheets (hiPSC-CCSs), loaded with a voltage-sensitive dye, and optically mapped. Arrhythmias were induced either spontaneously, using pacing interventions, or following drug applications. We examined two algorithms to detect spiral wave arrhythmias: optical flow (OF) and dominant frequency (DF). OF enables flow detection through spatial analysis of local velocity vectors (Fig.1 a-d). DF maps depict the frequency with the highest energy in each pixel (Fig.1 e-f). Spiral waves were readily detected by both approaches by the presence of significant diversity in both the frequencies maps (DF) and in the velocity angles (OF). Moreover, in DF maps, the core of the spiral wave (singularity point) could be identified as pixels displaying high dominant frequency as compared to values in other parts of the specimen. (Figure 1). Finally, EADs could be detected using a curve-fitting approach (Fig.1g).

Figure 1:
(a-d)
Consecutive optical map frames (a, c) and velocity vector maps (b, d) of normal (a, b) and a spiral wave (c-d) propagations.
(e-f )
DF maps of normal (e) and spiral wave (f) propagations.
(g)
EAD detection in red.

Conclusion:
Automatic algorithms were developed to enable robust detection of arrhythmic activity (EADs and spiral waves) in a hiPSC-based cardiac tissue model. This novel approach may bring a unique value to arrhythmia mechanistic studies, high throughput drug screening, and disease modeling.
Abstract 14311: Gene Guided Antiplatelet Therapy for Acute Coronary Syndrome: An Updated Meta-Analysis
Authors: Balasubramanian Senthil S , TANGRI APOORVA , Natarajan Arjun , Gaznabi Safwan , Qamar Arman
Published: April 2024

Introduction:
Clopidogrel has been the mainstay oral antiplatelet regimen to treat Acute Coronary syndrome (ACS) post percutaneous coronary intervention (PCI) with stents. However, there is marked inter-individual variability due to genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 in the antiplatelet effects of clopidogrel and a reduced response to this drug may be a risk factor for ischemic complications. There has been varied evidence in gene-guided antiplatelet therapy post PCI. An updated meta-analysis was conducted to study the effect of gene-guided antiplatelet therapy in ACS.

Methods:
A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 180 publications. Nine studies fulfilled inclusion criteria including 8 randomized clinical trials and 1 observational study. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were the composite major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction (MI), bleeding and cardiovascular (CV) death.

Results:
Gene guided antiplatelet therapy was performed in 7106 patients and conventional therapy in 3970 patients. The MACE events was significantly lower in gene-guided therapy arm (OR = 0.67, 95% CI [0.51 -0.87], P=0.003) driven by lower stent thrombosis (OR=0.47, 95% CI [0.25 -0.88], P=0.02) and lower MI in the gene guided therapy (OR=0.61, 95% CI [0.41 -0.92], P=0.02). The bleeding rates trended to be lower in the gene guided therapy as well (OR = 0.75, 95% CI [0.54-1.02], P=0.07). There is no significance difference in CV death. (OR=0.57, 95% CI [0.21-1.55])

Conclusions:
Genotype guided antiplatelet therapy in ACS has lower adverse cardiovascular outcomes driven by lower stent thrombosis and MI with lower bleeding trends as well.
Abstract 14320: High Density Lipoprotein Affinity and Transport of Small RNAs in Atherosclerosis
Authors: Michell Danielle L , Allen Ryan M , Semler Elizabeth , Cavnar Ashley , Raby Chase , Castleberry Mark , Ramirez Marisol , Zhao SHilin , Sheng Quanhu , Linton Macrae F , Vickers Kasey C
Published: April 2024

HDL have many alternative functions outside of cholesterol efflux likely due to its diverse cargo of proteins, lipids, and small non-coding RNAs (sRNA). We have reported that HDL transports microRNAs (miRNA) and other sRNA classes, including tRNA-derived sRNAs (tDR), which are produced during cell stress. We hypothesize that HDL-tDR transport is conferred by apolipoprotein A-I (apoA-I) RNA binding capacity. HDL-miRNAs have previously been shown to be altered in many diseases; however, changes to HDL-tDRs in diseases such as cardiovascular disease, have not been reported. Based on sRNA sequencing, tDR-GlyGCC was identified as one of the most abundant sRNAs on HDL and HDL-tDR-GlyGCC levels were found to be significantly increased in humans with advanced atherosclerosis, as determined by coronary artery calcium scores. Moreover, we found that macrophages readily export tDR-GlyGCC to HDL. To determine the binding properties of HDL-tDR-GlyGCC, microscale thermophoresis (MST) and electromobility shift assays were completed. HDL were determined to have the strongest binding affinity to tDR-GlyGCC (K
d
=48nM) compared to other sRNAs, including miR-223-3p (K
d
=372nM), suggesting that HDL has preferences for distinct sRNAs. As sRNAs can be post-transcriptionally modified, we investigated if RNA modifications inhibit HDL binding. Both 2-
O
-methylation and locked-nucleic acid modifications diminished HDL binding while other chemical forms of tDR-GlyGCC, namely dsRNA and ssDNA, were found to completely block binding. To determine if apoA-I confers RNA binding capacity of HDL, MST studies were completed on lipid-free apoA-I and single unilamellar lipid vesicles (SUV), and while apoA-I was found to bind moderately, SUVs failed to bind tDR-GlyGCC. Interestingly, reconstitution of SUVs with apoA-I rescued tDR-GlyGCC binding. Moreover, chemical cross-linking of 4-thiouridine-containing tDR-GlyGCC to apoA-I caused both protein size shift and dimerization as determined by western blotting. Crosslinked proteins were also used to uncover potential apoA-I RNA binding domains, as determined by LC-MS/MS. These results support that apoA-I RNA binding capacity confers HDL-tDR-GlyGCC acceptance from macrophages and transport in atherosclerosis.
Abstract 14327: Intramyocardial Delivery of an Imageable Theranostic Hydrogel Post Myocardial Infarction Alters Regional Strain and Reduces Remodeling in Chronic Porcine Model
Authors: Melvinsdottir Inga H , Midgett Dan , Lee Shin-rong , Uman Selen , Kim John , Avendano Ricardo , Thorn Stephanie , Lysyy Taras , Arnarsson Kristjan , Humphrey Jay D , Duncan James S , Burdick Jason A , Sinusas Albert
Published: April 2024

Introduction:
Myocardial infarction (MI) causes acute regional changes in stiffness and strain, resulting in pathological remodeling in the left ventricle (LV). Intramyocardial injection of hydrogel (HG) into the MI region may alter deformation and improve LV remodeling. Using high resolution cineCT (CCT) we evaluated changes in regional strain, global function, and geometry in chronic porcine MI model.

Methods:
Yorkshire pigs (n=12) subjected to 90 min balloon occlusion and reperfusion were randomized 5 days post MI to intramyocardial delivery of MI+HG (n=6) or MI only (n=6). Imageable HG was delivered in a 3x3 grid after assessing MI region with hybrid
201
Tl SPECT/CT. Contrast CCT was performed at baseline, day 5 (post MI before HG delivery), and day 12 (7 days post HG delivery) to assess end diastolic volume (EDV) and ejection fraction (EF). Custom software was used to calculate 3D myocardial Lagrangian strains on 6 HG animals and 3 MI only animals in remote, border (>50% normal) and MI regions (<50% normal).

Results:
At day 5 in both groups, EDV increased by 13.2% (p=0.016), LVEF decreased by 15.7% (p=0.008), and radial strain (E
rr
) decreased in MI region by -0.11 (p=0.007). On day 12, EDV decreased by 8.3% in the MI+HG group but increased by 10.4% in the MI only group (p=0.003). LVEF increased significantly in the MI+HG group by 8.96% and was significantly greater than in MI only group (p=0.027) which had no significant changes. Average change in E
rr
between baseline and day 12 was not different between groups within the MI (p=0.13) or border region (p=0.67). However, average E
rr
did not decline in the MI+HG group (+0.029) but significantly declined in MI only group (-0.14, p=0.017) (MI+HG vs MI only; p=0.003), mirroring EDV changes.

Conclusions:
Intramyocardial delivery of HG 5 days post-MI resulted in greater improvement in E
rr
in remote region and global LVEF and a decrease in EDV suggesting reduced LV remodeling compared to MI only controls.
Abstract 14331: Findings of a Novel Barbershop-Based Peripheral Artery Disease Screening Program and Intervention for Black Men
Authors: White Solaru Khendi T , RAVENELL Joseph E , Longenecker Christopher , Coy Tyler , Delozier Sarah J , Brinza Ellen , Wright Jackson T , Gornik Heather L
Published: April 2024

Introduction:
Peripheral artery disease (PAD) increases risk of cardiovascular events and limb events including amputations. Black race is a strong risk factor for PAD. Screening for PAD using the ankle-brachial index (ABI) can lead to early diagnosis and treatment. This is the first study to screen for PAD using the ABI in barbershops.

Hypothesis:
Barbershop-based screening and an educational intervention can detect PAD and increase PAD knowledge in a high-risk population.

Methods:
A screening pilot study was conducted at two barbershops in Cleveland from June-December 2020. Black male participants aged 40-89 completed an initial screening visit with automated ABI and a confirmatory visit with Doppler ABI. All were invited to watch an educational video on PAD and interviewed at 2-month follow-up. Automated blood pressure, health status, and knowledge about PAD were assessed at all visits.

Results:
37 participants completed the initial screening, 31 (84%) completed the confirmatory testing visit, 29 (78%) completed the exit visit, and 27 (73%) watched the educational video. After screening with both automated and Doppler ABI, PAD was identified in 5/31 (16.1%) participants. PAD awareness was low, but among those who completed the study, 23 (82%) showed improved PAD awareness scores as well as improvement in their self-assessed knowledge of PAD (
p<
0.001). An association was found between good PAD awareness at baseline and education: compared to those with some college education, those who did not graduate high school scored lower on PAD awareness (
p
= .022), as did those who only had a high school diploma or GED (
p
= .049).

Conclusions:
In a pilot study, barbershop-based screening for PAD among Black men revealed a higher than expected PAD prevalence and low PAD awareness. ABI screening and an educational video increased PAD awareness. ABI screening and educational outreach in the barbershop may be effective tools to diagnose PAD and increase awareness among Black men.
Abstract 14332: Interrelationship of Thromboinflammatory Biomarkers in the Pathogenesis of Atrial Fibrillation
Authors: Fareed Jawed , Dungan Gabriel , Odeh Ameer , Bontekoe Emily , Hoppensteadt Debra , Siddiqui Fakiha , Iqbal Omer , Lewis Joseph , Syed Mushabbar
Published: April 2024

Introduction:
Atrial Fibrillation (AF) is the most prevalent cardiac arrythmia and is one of the main causes of cardiovascular morbidity. There is a growing role of thromboinflammatory processes in the pathogenesis of AF. This vascular remodeling can be attributed to the static and/or turbulent flow within the left atrium due to ineffective atrial contraction, triggering endothelial cell injury and the generation of inflammatory cytokines. AF induced atrial inflammation exerts a pro-inflammatory effect on endothelial cells, resulting in endothelial activation and dysfunction which prompts the vasculature towards a pro-thrombotic state. This study seeks to examine the potential relationship between various thrombotic and inflammatory biomarkers in AF patient plasma.

Materials and Methods:
Citrated blood samples from 111 AF patients with confirmed clinical diagnosis of atrial fibrillation were enrolled in this study. Control plasma samples represented 50 healthy male and female individuals. All samples were analyzed using commercially available ELISA methods for the thrombotic biomarkers vWF, tPA, PAI-1, the inflammatory biomarkers IL-6, IL-8, TNFa, CRP, and the biomarkers Renin and Ang-I which highlight RAAS involvement in blood volume regulation. All results were tabulated and correlation analysis between each respective biomarker was carried out using GraphPad prism software.

Results:
All of the biomarker studies showed varying levels of increase in patient plasma as compared to normal controls. The AF patients showed a statistically significant Pearson correlation between the following biomarker pairings: vWF vs IL-8 (r=0.488, p=0.04), Renin vs TNFa (r=0.679, p=0.005), Ang-I vs TNFa (r=0.667, p=0.003), CRP vs IL-6 (r=0.665, p<0.0001), TNFa vs IL-6 (r=0.592, p=0.001), tPA vs PAI-1 (r=0.457, p=0.015).

Conclusion:
These studies suggest the coordinated expression of thrombotic and inflammatory mediators in the pathophysiology of atrial fibrillation. Profiling patient levels of these markers may be helpful in designing optimal therapeutic approaches for AF