bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13977: Identification of Intermediate Right Ventricular Phenotypes Using Consensus Clustering in Patients With Pulmonary Hypertension
Authors: Janowski Alexandra M , Ravellette Keeley , Garcia Joe G , Rischard Franz , Vanderpool Rebecca
Published: April 2024

Introduction:
Current right ventricular (RV) function phenotypes in pulmonary hypertension (PH) rely on few hemodynamic parameters to quantify RV dysfunction disease severity. The aim of the study was to identify novel RV phenotypes using RV hemodynamics and unsupervised machine learning in patients with PH.

Methods:
Participants were identified from the UArizona PH Registry (n=190). Correlation analyses identified 9 RV variables to include in clustering analysis. Consensus clustering was used to identify an unsupervised clustering method with a large inter-cluster, and small intra-cluster distance (Fig 1A). Significance was tested with Dunn and chi-square tests.

Results:
K-Medoids with a Pearson distance matrix over >1000 resampling iterations identified 5 clusters (consensus range: 0.8-0.9). World Symposium PH groups were distributed across clusters (Fig 1B). Clusters 1, 2 and 5 exhibit mild RV dysfunction with low diastolic stiffness (Eed) and afterload (Ea, Fig 1C). However, RV-PA coupling (Ees/Ea) was decreased in clusters 1 and 5. Clusters 3 and 4 have moderate to severe RV dysfunction with increased Eed and Ea but cluster 4 had decreased Ees/Ea. For pulmonary hemodynamics, clusters 3 and 4 have increased mean PA pressure (mPAP), increased pulmonary vascular resistance (PVR) and decreased PA compliance (Ca) compared to clusters 1 and 2. Cluster 5 has increased mPAP and high cardiac output resulting in moderately elevated PVR and decreased Ca.

Conclusions:
Unsupervised clustering identified 5 unique RV phenotypes ranging from mild to severe dysfunction. Further investigations are needed to identify factors modulating intermediate phenotypes to provide insight into RV dysfunction and disease progression.
Abstract 13984: The Feasibility and Safety of Left Bundle Branch Pacing in Patients With Tricuspid Valve Disease
Authors: Chen Xueying , Chen Jiahui , SU YANGANG
Published: April 2024

Background:
Although left bundle branch pacing (LBBP) has emerged as a novel physiological pacing strategy, it is still challenging in cases with tricuspid valve disease. Meanwhile, the influence of LBBP lead on tricuspid regurgitation has not been well established in these patients. In the present study, we evaluate the feasibility and safety of LBBP in patients with tricuspid valve disease.

Methods:
We enrolled 24 patients with tricuspid valve disease who received LBBP procedure in Zhongshan Hospital, Fudan University, between January 2018 and July 2020. Regular follow-ups were conducted (at 1 and 12 months), and the echocardiography data of the patients were collected and analyzed.

Results:
One postoperative lead dislodgements (1/24, 4.2%) occurred during the follow-up. Mean fluoroscopy time of placing LBBP lead was 19.75±08.23 minutes. Mean follow-up period was 9.64±4.17 months. Pacing parameters were stable during follow-up in all cases. The severity of tricuspid regurgitation(TR) (no 0, slight 1. mild 2, medium 3 and severe 4) under echocardiography were measured and compared at baseline and 1-year follow-up post-procedure. No significant aggravation occurred (2.88±1.57 vs 3.00±1.44, P=0.13). Left ventricular ejection fraction remain stable from baseline to 1-year follow-up(56.27±11.73% vs 59.30±8.17%, P=0.09).

Conclusion:
LBBP was feasible and safety in patients with tricuspid valve disease though these cases were always challenging such as longer fluoroscopy time, more technocratic requirements, higher rates of failure and procedure-related complications than HBP. Lead parameters were stable during follow-up. No significant aggravation of TR was found.
Abstract 13992: Cardiovascular Disease Risk of Abnormal Glucose Tolerance Depends on Etiology: Insulin Resistance versus Beta-Cell Failure
Authors: Wentzel Annemarie , Ishimwe MC Sage , Osei-Tutu Nana H , Hormenu Thomas , Patterson Arielle C , DuBose Christopher W , Sumner Anne E
Published: April 2024

Background:
Cardiovascular disease (CVD) and abnormal glucose tolerance (Abnl-GT) are rapidly increasing in sub-Saharan Africa. Abnl-GT is a primary risk factor for CVD. Yet, different Abnl-GT etiologies, insulin resistance (IR) or β-cell failure, may have different CVD risk profiles. Therefore, in 493 African-born Blacks living in the United States [male: 64%, age: 38±10y (mean±SD)], we evaluated the CVD risk profile within each Abnl-GT etiology.

Methods:
OGTT were performed. Abnl-GT, a term combining diabetes and prediabetes, was defined as fasting plasma glucose (FPG)≥100 mg/dL and/or glucose at 2h≥140 mg/dL. IR was defined by the upper quartile of HOMA-IR (≥2.03). Abnl-GT-IR required both Abnl-GT and IR. Abnl-GT-β-cell failure was defined as Abnl-GT without IR. Fasting lipids, including high-density lipoprotein (HDL), low-density lipoprotein (LDL) particle sizes, were measured. Dyslipidemia was defined as total cholesterol, TC>200mg/dL, LDL>130mg/dL, HDL<35mg/dL and triglycerides, TG>150mg/dL or any combination thereof. CVD risk was determined by the Pooled-Cohort Equation (PCE) [age, TC, HDL, SBP, diabetes, smoking status], as developed in the ARIC cohort.

Results:
Abnl-GT occurred in 37% (183/493) of participants, with Abnl-GT due to IR in 28% (69/183) and β-cell-failure in 62% (114/183). Neither systolic nor diastolic BP differed between the Abnl-GT groups (both
P
>0.05). HDL, HDL-size and LDL-size were lower and TG higher in the IR group compared to the β-cell-failure group (all
P
<0.01). The prevalence of dyslipidemia was higher in the IR than the β-cell-failure group at 49% (34/69) vs 28% (32/114) (
P
<0.05). The IR had a higher PCE score versus the β-cell failure group [26.5±2.7 vs 18.8.0±1.9 (
P
=0.001)].

Conclusions:
Although IR was a less common cause of Abnl-GT than β-cell failure, the IR group had a more adverse lipid profile and therefore a higher CVD risk compared to the β-cell failure group. Thus, the etiology of Abnl-GT should be taken into account when developing treatment strategies for patients at higher CVD risk.
Abstract 13996: Retention of the NLRP3 Inflammasome-Primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-Induced Granulopoiesis
Authors: Sreejit Gopalkrishna , Nooti Sunil , Jaggers Robert M , Athmanathan Baskaran , Park Ki Ho H , Al-Sharea Annas , Johnson Jillian , Dahdah Albert , Lee Man KS , Ma Jianjie , Murphy Andrew , Nagareddy Prabhakara R
Published: April 2024

Background:
Excessive infiltration of neutrophils to the ischemic heart after an acute myocardial infarction (MI) is mediated in-part by the S100A8/A9-NLRP3-IL-1β signaling axis in neutrophils. Despite upregulation of NLRP3 inflammasome signaling components in neutrophils, the serum levels of IL-1β, was not impacted by MI suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils.

Methods:
Using parabiosis techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in one of the parabiotic mice and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in non-infarcted parabionts. Finally, we studied the molecular mechanisms that govern reverse migration and retention of primed neutrophils, IL-1β secretion and granulopoiesis. Cardiac function was assessed by echocardiography.

Results:
MI promotes granulopoiesis in the BM and introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited granulopoiesis in the non-infarcted parabionts. MI also promotes greater accumulation/ retention of inflammasome-primed neutrophils in the BM in a neutrophil CXCR4 (C-X-C-motif chemokine receptor 4) and serum S100A8/A9 dependent manner. In the BM, the primed neutrophils secrete IL-1β through formation of gasdermin D pores and, promote granulopoiesis. Strategies aimed at inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and, improved cardiac function.

Conclusions:
Our data reveals a new paradigm of how circulatory cells can deliver signaling molecules (e.g., IL-1β) directly to the site of action rather than through systemic release. The absolute requirement of signal-2 in the BM for IL-1β release is consistent with our model where neutrophils undergo programming in the infarcted heart and inertly return to the sites of production (i.e., BM) with cytokine cargo (i.e., IL-1β) to regulate granulopoiesis. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.
Abstract 13997: Thirty-Day Readmissions Rates and Causes Among Patients After Heart Transplant: Insights From the Nationwide Readmissions Database
Authors: Goyal Amandeep , Acharya Prakash , Pothuru Suveenkrishna , Lahan Shubham , Ranka Sagar , Dalia Tarun , Taduru Siva , Sauer Andrew J , Haglund Nicholas , Vidic Andrija , Shah Zubair
Published: April 2024

Introduction:
Heart transplantation (HT) is a treatment of choice for many patients with advanced heart failure who continue to deteriorate despite optimal medical therapy. Data on patient characteristics, predictors, and readmission rates after HT is limited. We sought to evaluate the causes and predictors of the 30-day readmission rate among HT patients.

Methods:
Using the Nationwide Readmission Database, we included adult patients (≥18 years old) who underwent HT between January 2016 to November 2018. Patients with dual organ transplants were excluded from the study. Thirty-day readmission rates, causes, and predictors of readmission were assessed.

Results:
We analyzed 7386 patients who underwent HT and discharged alive during the years 2016 to 2018. The mean age was 53.35 ± 12.97 years and 73% were males. The 30-day readmission rate was 22.4% (n=1647). Heart transplant rejection/failure was the main cause of readmission (16.3%) followed by systemic infections (13.2%), post-procedure transplant complications (10%), acute kidney injury (6.3%), and procedure-related wound infection (4.2%)
(Fig 1A)
. Using multivariate logistic regression the risk of 30-day readmission was higher in patients with high comorbidity burden if Elixhauser score
>
14 (OR 1.41: 95% CI 1.10-1.79) and in patients who have a length of stay > 30 days during index admission (OR 1.18: 95% CI 1.01-1.39). Female gender was also found to be an independent predictor of readmission (OR 1.33: 95% CI 1.09-1.61)
(Fig 1B)
.

Conclusions:
Readmission rate is high in orthotopic heart transplant patients and is driven mostly by graft rejection/failure, infections, and post-procedure-related complications. Pre-transplant identification of high-risk patients will help in improving outcomes.
Abstract 14110: Inhibition of Lpl and CD36 Does Not Prevent Lipid Accumulation in the Hearts of Adipose Triglyceride Lipase (ATGL) Deficient Mice
Authors: Oluwadare Babajide , Gonzalez Cabodevilla Ainara , Son Ni-Huiping , Goldberg Ira J
Published: April 2024

We tested whether murine ATGL deficiency-induced cardiotoxicity would be prevented by reducing uptake of circulating lipids through inhibition of lipoprotein lipase (LpL) or the fatty acid transporter CD36. Mice were created with floxed alleles for
Atgl
and
Lpl
and expression of MHC-Cre. Triglyceride content in the heart was 10x greater in the
Atgl
KO mice compared to control, and concurrent
Lpl
deletion did not change that. The
Lpl Atgl
DKO hearts had a comparable gross appearance and similar weights to the
Atgl
KO mice. The mice also had a similar survival rate with early death beginning at ~12 weeks. We then hypothesized that non-esterified fatty acids rather than triglyceride-derived fatty acids were the source of lipids in
Atgl
deficient hearts. To test this, we reduced CD36 expression using an antisense oligonucleotide (ASO) and also by creating heart specific combined
Atgl
and
Cd36
knockout mice. The ASO knocked down CD36 expression in both CD31 (endothelial cells) and non-CD31 cells from the heart. It also reduced starvation lipid droplet formation and accumulated heart lipids after 3 weeks of a high fat diet. Surprisingly, neither the ASO nor genetic knockout rescued the
Atgl
deficient hearts from lipid accumulation or prevented early mortality. Placing mice on high fat (60%) or high sucrose (40%) diets also did not alter the development of heart dysfunction. We then hypothesized that the lipid accumulation with ATGL deficiency could occur independent of access to exogenous lipids. We tested this in vitro using H9c2(2-1) rat cardiomyocytes. After an overnight incubation in serum-free medium to deplete lipid droplets, inhibition of ATGL with Atglistatin led to cardiomyocyte accumulation of lipid droplets in the absence of a lipid source in the media. Concurrent inhibition of fatty acid synthase (FASN) with C75, cerulenin, or platensimycin prevented lipid droplet accumulation. Together, our data suggest that ATGL deficient lipid accumulation and toxicity can occur exclusive of lipid uptake.
Abstract 14112: Outcomes of Subcutaneous Implantable Cardioverter-Defibrillator Procedures in Obese versus Non-Obese Patients: A Retrospective Cohort Study
Authors: Hoster Clay , Huang Henry , Larsen Timothy , Krishnan Kousik , Trohman Richard , Peigh Graham , Verma Nishant , Sharma Parikshit , Wasserlauf Jeremiah
Published: April 2024

Introduction:
Obesity has been proposed as a risk factor for failed subcutaneous implantable cardioverter-defibrillator (S-ICD) shocks due to increased impedance associated with subcutaneous fat. Optimal implant technique, consisting of limiting subcutaneous fat underneath the coil and generator as well as posterior positioning of the generator, may overcome this barrier to successful conversion of ventricular fibrillation (VF) in obese patients.

Hypothesis:
Optimal S-ICD implant technique can result in successful defibrillation testing regardless of body mass index (BMI).

Methods:
Consecutive patients who underwent S-ICD placement and defibrillation testing at Rush University Medical Center between 2015-2021 were included. Defibrillation testing consisted of a 65 J shock after closure of the deep layer of the incision. Baseline demographics, procedural data, and chest radiographs were examined. A PRAETORIAN score was calculated based on distance between the coil and sternum, pulse generator to ribs, and posterior generator position. A PRAETORIAN < 90 has been associated with low risk of conversion failure in prior studies. The primary endpoint was the rate of successful first conversion of VF in obese versus non-obese patients.

Results:
The study included 35 patients. Mean age was 44 ± 13 years, 60% were male, and 51.4% were obese (BMI ≥ 30). Mean PRAETORIAN scores for obese and non-obese patients were 84.7 ± 65.8 and 49.3 ± 31.3, respectively (p=0.067). There were 7 obese and 1 non-obese patients with a score ≥ 90 (p=0.041). Mean shock impedance was 69.3 ± 22.2 Ω and 60.9 ± 20.7 Ω, respectively (p=0.259). There were 3 (16.7%) failed initial shocks in obese patients, and 0 failed initial shocks in non-obese patients (p=0.23). All three obese patients with failed initial shocks had scores ≥ 90 (90, 150, 225). A second 65 J defibrillation test was successful in each of these cases with shock polarity reversal.

Conclusions:
In this single center study, a PRAETORIAN score < 90 was associated with successful initial conversion from ventricular fibrillation in all obese and non-obese patients. The findings suggest that using optimal technique, a successful implant can be achieved regardless of BMI. Additional multi-center data collection is ongoing.
Abstract 14113: Age-Related Demographic Trends in Mortality Due to Ischemic Heart Disease in the United States From 1999 to 2019
Authors: Essa Mohammed , Ghajar Alireza , DeLago Augustin , Hammond-Haley Matthew , Shalhoub Joseph , Marshall Dominic , Salciccioli Justin , Sugeng Lissa , Philips Binu , Faridi Kamil
Published: April 2024

Introduction:
United States Ischemic heart disease (IHD) mortality has decreased recently. mortality trends for demographic groups across different ages have not been well described.

Hypothesis:
Different age groups have different IHD mortality trends

Methods:
WWe performed a nationwide analysis using the CDC WONDER database to evaluate IHD mortality trends from 1999 to 2019. Crude mortality rates per 100,000 were evaluated by sex, race, ethnicity and ten-year age groups. We used Joinpoint linear regression to assess average annual percentage change (AAPC) in IHD-related mortality.

Results:
From 1999 to 2019, IHD mortality decreased from 189.8 to 110.0/100,000 (AAPC -2.9%, 95% CI -3.3 to -2.6%) nationally. Compared to the 65-74 year age group (AAPC -1.7%, 95% CI -1.9 to -1.4%), decline in IHD-related mortality was lower for 35-44 year (-0.4%, 95% CI -0.4 - 0.0%; p < 0.001), 45-54 year (-0.4%, 95% CI -0.5 to -0.3%; p < 0.001), and 55-64 year (-0.5%, 95% CI -0.8% to -0.2%; p < 0.001) age groups but similar for the 75-84 year group and higher for ≥85 year age group. Black populations had the highest mortality rates among men and women across all age groups except men ≥85 years old. All the studied groups had significant decreases in mortality between 2002 and 2010. From 2010 to 2019, all groups had significant decreases in mortality except for 35-44 year-old minority groups (black women AAPC -0.7%, 95% CI -2.3% to 1.0%; black men -0.6%, 95% CI -1.7% to 0.6%; Hispanic women 0.9, 95% CI -1.7% to 3.6%; Hispanic men 0.3%, 95% CI -0.9% to 1.5%) (Figure).

Conclusions:
U.S. populations <65 years old have had slower declines in IHD-related mortality than those ≥65 years, and black populations continue to have the highest IHD-related mortality across almost all age groups. Since 2010, black and Hispanic populations between 35 and 44 years old have not had significant decreases in IHD-related mortality. Greater focus on prevention and treatment of IHD in younger and minority populations is needed.
Abstract 14114: Role of Toxic Protein Sequestration by Aggregates in Cardiac Myocytes in Ischemic Cardiomyopathy
Authors: Islam Moydul , Rawnsley David , Ma Xiucui , Foroughi Layla , Zhao Chen , Murphy John , Jackrel Meredith , Weinheimer Carla , Kovacs Attila , Javaheri Ali , Razani Babak , Diwan Abhinav , Mani Kartik
Published: April 2024

Introduction:
Proteotoxic aggregation causes cardiomyopathy (CMP) associated with rare genetic mutations. The role of protein aggregates in ischemic cardiomyopathy is unclear.

Hypothesis:
Cardiac myocyte protein aggregation is deleterious in cardiomyopathy.

Methods:
Human (ischemic) and murine (ischemic and proteotoxic) CMP models were profiled by immunohistochemistry (IHC) and proteomic characterization of the detergent-insoluble fraction. Aggregates were evaluated by immunocytochemistry in p62 deficient neonatal mouse cardiac myocytes (NMCMs) with adenoviral transduction of mutant alpha-B crystallin (CRYABR120G). Mice with cardiac myocyte selective p62 deficiency (p62ckO) were generated and characterized (echocardiography, myocardial structure, autophagic flux, mitophagy, and biochemical analyses). p62cKO and floxed controls were subjected to closed-chest ischemia (90 minutes) or sham followed by reperfusion (IR) and evaluated 4 weeks later. Cardiac selective (AAV9-cTnT) reconstitution of p62, its aggregation-deficient K7R mutant or GFP, was performed. Wild-type mice transduced with a fungal disaggregase (AAV9-Hsp104 or control) were modeled for IR as above.

Results:
Protein aggregation increases in ischemic CMP, but not controls, with
increased insoluble
CRYAB with phosphorylation at serine 59 (pS59CRYAB). p62-deficient NMCMs are unable to form aggregates following CRYABR120G transduction, indicating the necessity of p62 in protein aggregation. p62cKO mice show preserved baseline cardiac structure/function, without significantly decreased mitophagy or autophagic flux. Compared to controls, p62cKO mice (post-IR) show infarct expansion and impaired LV remodeling at 4 weeks, associated with
decreased sequestration of
pS59CRYAB in insoluble fraction. Reconstitution with AAV9 p62, but not aggregation-deficient K7R, shows partial functional rescue after IR. Finally, disruption of protein aggregation by AAV9 Hsp104 (but not controls) results in
decreased sequestration
of
pS59CRYAB, and decreased function post-IR.

Conclusions:
Contrary to the hypothesis, preventing or disrupting protein aggregation, associated with decreased pS59CRYAB sequestration, is maladaptive in ischemic cardiomyopathy.
Abstract 14127: Gene Level Data Extraction, Integration and Comparison of Preclinical Atherosclerosis Investigations in the ApoE and LDLR Knockout Mouse Models
Authors: Xiang Rachel R , Moss M. Elizabeth , Carvajal Brigett V , Wang Yihua , Camarda Nicholas , Stepanian Alec , Ramsey Jacob , Shuey Megan M , Wells Quinn , Beckman Joshua A , Jaffe Iris Z
Published: April 2024

Introduction:
Animal models are extensively used to interrogate molecular mechanisms of disease. The apolipoprotein E knockout (ApoE-KO) and low-density lipoprotein receptor (LDLR)-KO mouse models are well established preclinical models of atherosclerosis.

Hypothesis:
We hypothesized that integrated analysis of preclinical data will identify novel signaling pathways and regulatory networks driving atherogenesis. Comparison of findings between models may implicate model-specific mechanisms of atherosclerosis.

Methods:
Data were extracted from 716 ApoE KO and 422 LDLR KO manuscripts published in
ATVB
journal from 1995-2020. Extracted data described the impact of an experimental gene perturbation on atherosclerotic phenotypes. Impacts on plaque size and composition were analyzed using Ingenuity Pathway Analysis, separately for each model and as an aggregate dataset.

Results:
Distinct regulatory pathways and networks were identified across models and in early versus late stages of atherosclerosis. Of top networks in each model, 8/10 were inflammatory and cell growth networks in the ApoE-KO whereas 6/10 were lipid and carbohydrate metabolism networks in the LDLR-KO dataset. Integration of data identified SC-58125, a cyclooxygenase-2 inhibitor, as the top regulatory network that linked 53% (n=168) of genes implicated in atherosclerosis into a single network. Aggregate data from early atherogenesis (<11 wks. high fat diet (HFD)) was enriched in inflammatory functions, whereas late atherosclerosis (14+ wks. HFD) was associated with cell growth and metabolic pathways.

Conclusion:
Integration of data from two genetic KO mouse models identified distinct gene programs driving atherosclerosis in each model system. Aggregation of data from two models strengthened key findings and identified novel associations. Finally, combining datasets provided greater power to identify distinct gene pathways and networks in early versus late atherosclerosis.
Abstract 14135: Impact of Increasing Left Ventricular and Left Atrial Size on Echocardiographic Measurements in Patients With Non-Ischemic Cardiomyopathy
Authors: Turkmani Mustafa , Liu Gui Ting , Wang Tom K , Salam Donna , Tang Wai Hong W , Griffin Brian P , Flamm Scott D , Kwon Deborah H
Published: April 2024

Background:
Echocardiography is the primary imaging modality for assessment of patients with non-ischemic cardiomyopathy (NICM), but it is known to underestimate cardiac magnetic resonance (CMR) measurements of LV volumes. We sought to assess the impact of increasing left ventricular end-diastolic volume index (LVEDVi) and left atrial volume index (LAVi) on the accuracy of echocardiographic measurements, when compared to CMR.

Methods:
NICM patients undergoing CMR between 4/4/2001-12/29/2017 with echocardiography measurements that were obtained within 90 days were retrospectively recorded. Bland Altman analysis and Pearson’s correlation were performed to compare echocardiographic and CMR assessment. Multivariable logistic regression analysis was also performed to predict Echo bias > 50cc/m2 for LVEDVi.

Results:
Echocardiographic and CMR measurements of LVEDVi and LAVI were obtained in 390 and 400 patients, respectively. Figure 1 illustrates the Bland Altman and Pearson’s correlation of echo vs CMR measurements of LVEDVi and LAVi. While echo and CMR LVEDVi and LAVi were significantly correlated (r=0.762 and 0.605, respectively), there was significant increase in echocardiographic underestimation as the LVEDVi and LAVi as the left ventricle and left atrium increased in size. Multivariable logistic regression analysis is presented in Figure 1. There was a trend toward increased error in women (p=0.076), but age and BME were not significantly associated with increased echo underestimation. Increasing LVEDVi was the strongest predictor of echo underestimation (p<0.0001).

Conclusion:
Echo underestimation of LV and LA size in patients with NICM increases as the LV and LA size increases. Increased error in echocardiographic measurements may have significant clinical impact in regards to prognosis and procedural therapeutic management strategies.
Abstract 14143: In-Hospital Outcomes of Left Ventricular Assist Device Implantation in Patients With Heart Failure and Connective Tissue Disease
Authors: Grant Jelani , Hernandez Rafael , Gilchrist Juliann , Maning Jennifer , Vincent Louis T , Ebner Bertrand , Olorunfemi Odunayo , Colombo Rosario A
Published: April 2024

Introduction:
The use of left ventricular assist devices (LVAD) for patients with end-stage heart failure (HF), either as a bridge to transplant or destination therapy, continues to grow. Optimal patient selection is essential to decrease the risk of adverse events. The aim of our study was to evaluate outcomes of LVAD in patients with HF and connective tissue disease (HF-CT).

Methods:
Using the National Inpatient Database (NIS) we identified patients 18 years and older hospitalized for index LVAD procedure from 2016 to 2018. Patients were stratified according to CT disorder status. The primary outcome of interest was in-hospital mortality. Secondary outcomes included the need for renal replacement therapy (RRT), post-operative infection, stroke, and transfusion requirements. A multivariate regression analysis model was used to adjust for statistically significant differences in baseline characteristics between the groups.

Results:
A total of 30,206 patients underwent LVAD implant, of these 240 (0.8%) had CT disease. HF-CT patients were more likely to be female (47.5% vs 23.2%, p < 0.001), less likely to have pulmonary hypertension (12.5% vs 21.1%, p = 0.001) and liver disease (2.2% vs 9.5%, p < 0.001); and more likely to have anemia (18.4% vs 12.2%, p = 0.009). There was no significant difference in in-hospital mortality (8.3% vs 11.9%, p = 0.090). Unadjusted incidence of stroke (21.1% vs 7.4%, p = 0.002) and renal replacement therapy (2.1% vs 6.7%, p =0.090) was lower for HF-CT patients. However, this difference was not related to the presence of CT disease on multivariate analysis.

Conclusions:
While some studies have raised concerns of increased adverse events among patients with HF-CT undergoing LVAD implant, our analysis showed that in-hospital survival and short-term post-operative outcomes of HF-CT patients appear to be comparable to patients without CT disease. A clinical history of CT disease by itself should not preclude patients from undergoing LVAD implant.
Abstract 14149: Access to Neurology and Telestroke Services in Rural America
Authors: Machado Sara , Ulep Robin , Southerland Andrew M , Vaduganathan Muthiah
Published: April 2024

Introduction:
Stroke and other neurologic diseases may disproportionately affect persons in rural areas, and stroke-related mortality in rural counties has increased in recent years. Little is known about distribution and trends in neurologists and telestroke services in rural vs urban counties in the US.

Methods:
Volume and age distribution of neurologists in each county were determined using the AMA Physician Masterfile for each year 2010-2018. Neurologist density (per 100,000 persons) was estimated based on county-level population data. Telestroke units per county were identified using Area Health Resource files. Counties were classified as large metropolitan, medium or small metropolitan, or rural based on CDC WONDER designations.

Results:
From 2010-2018, mean (SD) neurologist density in rural counties decreased from 6.3 (21.6) to 5.9 (18.7) per 100,000 persons. A majority of rural counties experienced little to no change (0-5 per 100,000) in neurologist density over time. In contrast, neurologist density increased in large metropolitan counties from 31.1 (42.7) to 37.8 (52.1) per 100,000 and in medium/small metropolitan counties from 29.3 (67.8) to 32.2 (74.9) per 100,000. Over time, 42% of large metropolitan and 27% of medium/small metropolitan counties experienced >10 per 100,000 longitudinal increases in neurologist density. The proportion of younger neurologists (<35 or 35-44 years) appeared to increase in urban counties, while the proportion of older neurologists (≥65 years) relatively increased in rural counties. In 2018, telestroke units were available in 51%, 37%, and 18% of large metropolitan, medium/small metropolitan, and rural counties, respectively.

Conclusions:
Neurologist density has decreased in rural counties in the US, with a relative aging of existing neurologists in these settings. Four out of 5 rural counties do not have telestroke units. These data underscore the need to improve access to neurology in rural areas.
Abstract 14161: Drug Compounds Combination Screening Using Human Induced Pluripotent Stem Cell-Derived Cardiac Tissues
Authors: Landesberg Michal , Wexler Yehuda , Huber Irit , Gepstein Amira , Arbel Gil , Gepstein Lior
Published: April 2024

Introduction:
The introduction of human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) technology provided an important tool for the field of safety pharmacology (QT screening). This approach has been limited, however, mostly to the assessment of a single drug. We present a large scale EP phenotyping system comprised of hiPSC-derived cardiac cell sheets (hiPSC-CCSs), fluorescent voltage sensors and actuators, and an optical mapping system; with the aim of performing drug combination screening.

Methods and Results:
hIPSCs-CMs were seeded as hiPSC-CCSs in multi-well plates. Tissues were treated with varying concentrations of drug compounds’ combinations. Optical signals were acquired following loading of the hiPSC-CCSs with voltage-sensitive dyes or expression of genetically-encoded voltage indicator (ArcLight). EP parameters such as conduction velocity (CV) and action potential duration (APD) were extracted. ATX2 (late sodium current activator) and Dofetilide (IKr blocker) were chosen as representative APD prolonging reagents. Example of the effects of 16 different drug doses combinations on APD (% change) prolongation is depicted in Fig.1a. Similarly, examples of the restitution plots obtained at 4 different drug combinations are presented in Fig.1b-c. Notice that drug compound's effect on prolonging APD showed greater effect as compared to the cumulative effect of each drug alone.

Figure 1:
(a)
Percentage of change in APD
80
15 minutes post treatment
(b, c)
APD
80
per condition before and after treatment, respectively

Conclusion:
These results highlight the potential of the hiPSC-CCS as a model for combinational drug screening. This may bring a unique value to the fields of safety pharmacology, pathophysiology testing and drug screening applications.
Abstract 14180: RyR2 Hyperactivity Contributes to Arrhythmogenic Triggers in the
ex vivo
Human Right Ventricle
Authors: Brennan Jaclyn A , Faye Rokhaya N , Knollmann Bjorn C , Efimov Igor R
Published: April 2024

Introduction:
Sudden cardiac death (SCD) caused by VT/VF is a major cause of mortality and morbidity, accounting for up to 20% of all deaths in the United States. Novel antiarrhythmic targets and relevant translational models of SCD are urgently needed for basic and translational arrhythmia research, and
ex vivo
donor human hearts are invaluable resources for such pharmacological studies. It was the goal of this study to investigate the occurrence of VT/VF in excised human hearts and to test a novel pharmacological agent to suppress arrhythmias.

Hypothesis:
We assessed the hypothesis that RyR2 hyperactivity contributes to arrhythmogenic triggers and substrates in the human RV, and we analyzed the antiarrhythmic effects of pharmacological RyR2 suppression.

Methods:
Adult human hearts (n = 10; 3F, 7M) were procured from the Washington Regional Transplant Community. The entire RV free wall was isolated, coronary perfused, and placed in an oxygenated, 37°C bath of Tyrode’s solution for optical mapping with the addition of Di-4-ANBDQBS and blebbistatin. Pseduo ECGs were recorded, and action potentials (APs) were spatiotemporally mapped using high-speed CMOS cameras. Optical recordings were taken at baseline and after exposure to the adrenergic agonist isoproterenol (ISO, 250 nM) and the adenosine antagonist caffeine (CAF, 200 μM) to elicit RyR2 hyperactivity. We also evaluated pharmacological RyR2 suppression (2 μM dantrolene) on arrhythmia inhibition.

Results:
ISO and ISO+CAF significantly shortened tissue APDs. ISO+CAF increased the incidence of PVCs at low pacing frequencies as well as increased the incidence of VT/VF at high pacing frequencies. We observed non-sustained arrhythmias in roughly a third of the hearts examined. No significant differences in conduction velocities were observed. While dantrolene did not return APDs to baseline conditions, it did significantly reverse the effect of caffeine on inducing PVCs.

Conclusions:
In conclusion, caffeine contributes to arrhythmogenic triggers in the
ex vivo
human right ventricle, and dantrolene may be used as a pharmacological tool to suppress RyR2 hyperactivity and thus prevent SCD.
Abstract 14182: Diverse microRNA Cargo is Essential for the Cardioprotective Effects of Therapeutic Extracellular Vesicles
Authors: Euscher Lindsey M , Mentkowski Kyle I , Julian Isabella , Eagler Lisa A , Lang Jennifer K
Published: April 2024

Background:
Extracellular vesicles (EVs) deliver their protein and RNA cargo across the plasma membrane of target cells to exert a functional response. Injection of cardiosphere-derived cell (CDC) EVs have been shown to reduce cardiomyocyte (CM) cell death and improve cardiac function in large and small animal models of myocardial infarction (MI) and ischemia-reperfusion. While several EV miRNAs (miRs) have been identified to play a role in cardioprotection, it has not yet been established whether miR cargo is necessary for the therapeutic benefit of EVs. We hypothesized that miRNA cargo is essential in CDC-EV mediated cardioprotection post-MI.

Methods:
CDCs were transfected with siRNA against Drosha, the initial endonuclease in the miR biogenesis pathway. EVs were isolated from serum-free media and characterized by size, morphology, and protein/miR expression as previously described. We examined the role of EV miRNA on target cell apoptosis, proliferation, angiogenesis, and gene expression using a series of
in vitro
assays. To determine if miR cargo is essential for the therapeutic efficacy of CDC-EVs
in vivo
, we induced acute MI in adult C57BL/6 mice and randomized them to receive 1) EVs, 2) miR depleted EVs or 3) vehicle control. LVEF was assessed by echo at 1- and 28-days post-MI and tissue samples processed for assessment of histological endpoints.

Results:
Transfection of CDCs with siRNA against Drosha reduces miRNA in CDCs and their EVs by 81±5% and 65±4%, respectively (mean ± SEM, t-test, p<0.001). miR depleted EVs failed to recapitulate the reduction in cardiomyocyte apoptosis, decrease in fibroblast proliferation, and enhancement in angiogenesis seen with control EVs. Furthermore, while intramyocardial administered CDC-derived EVs improved LVEF compared with vehicle control treated animals 28 days post-MI (62 ± 4% vs 44 ± 4%), mice treated with miR-depleted EVs demonstrated no significant difference in LVEF (42 ± 6%) compared with vehicle control (n=8 mice/group, mean ± SEM, p<0.05, one-way ANOVA).

Conclusions:
miR deficient human CDC-EVs are unable to recapitulate the cardioprotective effects seen with control extracellular vesicles, providing important insight into the mechanism of action of therapeutic EVs.
Abstract 14185: Acute Pacing Regimen Strengthens Engineered Human Cardiac Tissue
Authors: Rupert Cassady , Li Kelly , Cirilli Shannon , Li Xia , Campbell Stuart
Published: April 2024

Introduction & Hypothesis:
Engineered heart tissues (EHTs) formed from human induced pluripotent stem cell (hiPSC)-derived cardiomycoytes are a valuable tool for in vitro testing and new technology provides the ability to mechanically test EHTs multiple times to study their longitudinal behavior. We performed these studies to test the hypothesis that acute electrical stimulation of otherwise unpaced EHTs is sufficient to improve contractile properties.

Methods:
EHTs were formed from seeding hiPSC-cardiomycoytes and human cardiac fibroblasts on MyoPod™ scaffolds of decellularized adult porcine ventricular myocardium. EHTs were cultured, unpaced, for 3 weeks, and then mechanical testing was performed on a MyoLab™ instrument to obtain the baseline contractile phenotype. Testing was performed at culture length under 1 Hz field stimulation in Tyrode’s solution with 1.6 mM Ca
2+
. After approximately 45 minutes of equilibration, contractile properties were calculated by averaging 10 consecutive contractions. Five EHTs were tested over the course of five days. One EHT was returned to culture, in the same, unpaced conditions and re-tested after 3 days.

Results:
EHTs formed and beat spontaneously at approximately 1 Hz after three to five days in culture. All tissues followed 1 Hz pacing during mechanical testing. The EHTs tested a single time within a five-day window exhibited consistent contractile properties (figure, left) with time-to-peak (TTP) of 222 ± 8 ms and time to 50% relaxation (RT50) of 133 ± 4 ms. (Mean ± SEM, n=4). The EHT retested after three days exhibited a much higher force of contraction, increasing by 50% of its force on day 0 (figure, right) with a corresponding increase in TTP of 220 to 248 ms and stable RT50 of 145 to 147 ms.

Conclusions:
Taken together, these data demonstrate a remarkable stability of EHTs tested over the course of 5 days and a surprising increase in contractile force imparted by 2.5 hours of pacing at 1 Hz.
Abstract 14187: Differential Neutralization of Unfractionated and Low Molecular Weight Heparin by Andexanet Alfa
Authors: Lewis Joseph , Iqbal Omer , Jeske Walter , Hoppensteadt Debra , Siddiqui Fakiha , Fareed Jawed
Published: April 2024

Introduction:
Andexanet Alfa is an antidote for the neutralization of the bleeding effects of Direct Oral Anticoagulant (Direct Xa) agents such as Rivaroxaban and Apixaban. It represents a molecularly modified factor Xa decoy protein with high specificity for factor Xa inhibitors. Unfractionated heparin (UFH) and low molecular weight heparins (LMWHs) exhibit both anti-Xa and anti-IIa activities. The purpose of this study is to investigate the relative neutralization of the anti-coagulant effects UFH and enoxaparin by andexanet alfa in whole blood assays such as activated clotting time (ACT) and thromelastography (TEG).

Methods:
The neutralization profiles of UFH and enoxaparin were studied by Andexanet at various concentrations. The final concentration of UFH used for activated clotting time (ACT) was 10 μg/ml, and for enoxaparin was 25 μg/ml. Andexanet was used in a concentration range of 12.5 ug/ml. For the thromboelastographic (TEG) analysis the concentration of all drugs were proportionately reduced. The results were analyzed using R open source statistical software. In order to compare the means of the groups, analysis of variance (ANOVA) tests were performed. If the ANOVA test yielded a significant result, a Tukey post-hoc analysis was performed. A pearson correlation was run for each parameter with respect to the dose of the drug.

Results:
Andexanet at 200 ug/ml moderately neutralized UFH (302 s vs 198). Andexanet minimally neutralized enoxaparin (200 s vs 190 s). There was no concentration dependent change in the neutralization profiles of UFH and enoxaparin at a concentration range of 12.5 ug/ml - 200 ug/ml. In the TEG assays, Andexanet alfa at 10 ug/ml partially neutralized the anticoagulant effects of UFH at 1 ug/ml as measured by various TEG parameters. At 20 ug/ml, stronger inhibition of all parameters were noted.

Discussion:
These studies suggest that Andexanet Alfa may be an effective neutralizing agent for UFH, however, it is ineffective in neutralizing LMWH at the concentrations studied. It is interesting to note that LMWHs have a higher anti-Xa to IIa ratio in comparison to heparin, however, their neutralization is lesser with Andexanet. These studies suggest that andexanet can be used in combination with protamine sulfate to neutralize UFH.
Abstract 14190: Cardiac Damage in COVID-19: An Undertreated Threat to Survival
Authors: Moretti Francesco , Baldi Enrico , Costantino Ilaria , Marangi Cosimo , Stagnitto Elisabetta , Leonardi Sergio , Camporotondo Rita , Oltrona Visconti Luigi , Gnecchi Massimiliano
Published: April 2024

Introduction:
Cardiac injury occurs in about 20-30% of patients hospitalized for COVID-19 and influence the prognosis but many aspects like the role of age and magnitude of cardiac damage in determining the prognosis, remains vague.

Hypothesis:
Age and magnitude of cardiac damage may influence the mortality of patients hospitalized for COVID-19.

Methods:
We considered all patients consecutively admitted at a third-level European Hospital for COVID-19 between February and June 2020. Cardiac injury was defined as a high-sensitivity cardiac Troponin I (hs-cTnI) value greater than the upper reference limit (URL) of 47 ng/dL. Firstly, we analyzed the data by hs-cTnI across age tertiles (<62 years, 62-73 years and >73 years). Then, we compared patients with no-damage, mid-damage (hs-cTnI up to 10-fold URL) and high-damage (more than 10-fold URL). The primary endpoint was in-hospital mortality.

Results:
We enrolled 543 patients (median age 69, 67% males); hs-cTnI was available in 509. The survival was lower in elderly patients and high levels of hs-cTnI worsened the prognosis across all age tertiles (Fig. 1A). Surprisingly, the magnitude of cardiac damage did not influence the overall in-hospital mortality (Fig. 1B), but patients with high-damage died earlier (survival at 15 days: 86% no-damage vs 61% mid-damage vs 49% high-damage; p<0.001). Of note, among patients with high-damage, only 7 received coronary angiography, cardiac magnetic resonance or heart biopsy.

Conclusions:
Cardiac injury dramatically increased the mortality across all ages in patients hospitalized for COVID-19. The magnitude of cardiac damage did not influence overall in-hospital mortality but almost all patients with high-damage died within 15 days from admission. A second-level diagnostic test was performed seldomly in high-damage patients, suggesting that the unexpected high burden of the first COVID-19 wave negatively influenced the health system and our clinical daily practice.
Abstract 14202: Perioperative Metabolites Are Associated With Neurodevelopmental Outcomes at One Year in Neonates Undergoing Cardiopulmonary Bypass
Authors: Heibel Jessica , Reuland Carolyn , Graham Eric M , ROUX Aurelie , Graham David , Manlhiot Cedric , Everett Allen D
Published: April 2024

Introduction:
Improving neurodevelopmental (ND) outcomes for children with congenital heart disease has become a priority. Known clinical and surgical risk factors do not fully capture differences in ND outcomes. The objective of this study was to determine if plasma metabolites at the time of neonatal cardiac surgery were association with ND outcomes at 1 year.

Methods:
A secondary analysis of a clinical trial in 110 neonates undergoing cardiac surgery was performed. Plasma samples obtained pre-op, immediately post-op and at 12 hours post op had LC/MS/MS metabolomic profiling with a 193-plex targeted metabolite assay covering >366 metabolic pathways. Metabolite levels were compared to one-year neurodevelopmental outcomes measured by the Bayley Scales of Infant and Toddler Development III (BSID).

Results:
40/193 metabolites were detected and quantified for analysis. Regression models utilizing metabolites and metabolite features identified associations with cognitive (n=5), language (n=4) and motor (n=10) BSID composite scores. Enrichment analysis disease pathways included seizures (tyrosine and isoleucine) and indoxyl sulfate, a known neurotoxic product from tryptophan synthesis.

Conclusions:
Perioperative metabolites may serve as biomarkers for prediction of 1-year ND outcomes and provide a scientific basis for targeted interventions to optimize perioperative care.
Abstract 14212: Relationship Between Baseline Frailty Status and Benefits of a Novel Multidomain Physical Rehabilitation Intervention Among Older Patients Hospitalized With Acute Decompensated Heart Failure: The REHAB-HF Trial
Authors: Pandey Ambarish , Pastva Amy M , Duncan Pamela W , Nelson Michael , Kitzman Dalane W , Whellan David J , Mentz Robert J , Chen Haiying , Upadhya Bharathi , Reeves Gordon R
Published: April 2024

Background:
Physical frailty is common among older patients with acute decompensated HF (ADHF) and is associated with worse quality of life (QOL) and a higher risk of adverse CV events. In the REHAB-HF trial, a 12-week, multidomain physical function intervention improved functional status and QOL in older ADHF patients. Whether baseline frailty status modifies the benefits of the intervention remains unclear.

Objective:
Evaluate the interaction between baseline frailty and treatment effects of the physical function intervention in the REHAB-HF trial.

Methods:
Frailty status was assessed by the modified Fried criteria. Outcomes were change in physical function (Short Physical Performance Battery [SPPB] score and 6-minute walk distance [6-MWD]), QOL (Overall KCCQ score), and Geriatric Depression Scale (GDS) score at the end of the 12-week intervention. Association between changes in frailty score and rates all-cause hospitalization were assessed using adjusted linear regression models.

Results:
At baseline, among 337 participants (age: 72 y, 54% women) 57% were frail, and 43% were prefrail. At 12-week f/u, both prefrail and frail groups improved with the intervention; however, the frail group had significantly greater improvements over the prefrail group in SPPB score, 6MWD, and KCCQ (Table). A significant improvement was also noted in the GDS score with the intervention among frail but not prefrail participants (Table). In adjusted analysis, an improvement in frailty score at 12-weeks was significantly associated with lower rates of all-cause hospitalization in the 3 months following the intervention period (rate ratio [95%CI] = 0.65[0.55-0.76], p<0.001).

Conclusion:
ADHF patients with worse frailty status at baseline had greater improvement in functional status and QOL than those who were prefrail. Furthermore, improvement in frailty burden with the rehabilitation intervention was significantly associated with a lower risk of rehospitalization.