bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 18395: Urinary Metals as Novel Risk Factors for Incident Heart Failure and Subtypes in Indigenous Communities in the US: Evidence From the Strong Heart Study
Authors: Martinez-Morata Irene , Domingo Arce , Pichler Gernot , Garcia Pinilla Jose Manuel , Umans Jason G , Tellez-Plaza Maria , Devereux Richard B , Shimbo Daichi , Navas-Acien Ana
Published: December 2023

Introduction:
Chronic exposure to metals is an independent risk factor for CVD, yet the role of metal exposure on heart failure (HF) and HF subtypes remains understudied. Indigenous communities in the US suffer a high burden of CVD and have been historically exposed to moderate and high levels of environmental metals. In this study we evaluate the prospective association between urinary metal levels and incident HF and HF subtypes in the Strong Heart Study, the largest US cohort of American Indian adults.

Hypothesis:
We hypothesize that urinary metals are prospectively associated with increased HF risk, and the associations will be different for ejection fraction (EF) <50% and EF >50%.

Methods:
A total of 2,706 participants (mean (SD) age 56.4(8.1) years, 58% female) with urinary metals available at baseline (1989-1991) were included. Incident HF events were ascertained through 2019 by a physician panel, including classification of HF subtypes (EF50% and EF<50%). Progressively adjusted Cox proportional hazards models were used to identify the risk of incident HF and HF subtypes by an interquartile range (IQR) change in urine metals (Table 1).

Results:
A total of 444 participants developed HF (90 EF >50%, 127 EF<50%, 227 unclassified). Baseline levels of all metals were higher among participants who developed HF. In fully adjusted models (Model 2), higher levels of urinary cadmium, molybdenum and zinc were significantly associated with HF risk. The associations varied by HF subtype. While no significant associations were identified for those EF≥50%, higher levels of urinary tungsten, molybdenum, and zinc were significantly associated with HF EF<50% risk.

Conclusions:
We identified an association between baseline urine levels of several essential and non-essential metals and incident HF risk in the Strong Heart Study, with strongest associations for those with EF<50%. These findings can help identify novel modifiable risk factors of HF and inform prevention strategies.
Abstract 18397: Enhanced Ultrasound Imaging of Thrombotic Microvascular Obstruction Using GpIIb/IIIa-Targeting Gold Nanoparticles
Authors: Li Qin , chen miaona , Wu Juefei
Published: December 2023

Introduction:
Thrombotic microvascular obstruction (MVO) poses a diagnostic challenge due to the lack of specific imaging techniques in clinical practice. This study introduces a novel ultrasound imaging method that utilizes gold nanoparticles (AuNPs) modified with the GPIIb/IIIa-targeting peptide Arg-Gly-Asp (RGD) to enhance the contrast of ultrasound imaging for microembolization.

Methods:
Targeted gold nanoparticles (RGD-AuNPs) and untargeted gold nanoparticles (GSH-AuNPs) were synthesized using the glutathione reduction method from chloroauric acid. A rat model of MVO was established by infusing microthrombi into the left hindlimb via the right femoral artery. The rats were randomly assigned to receive either RGD-AuNPs or GSH-AuNPs injected via an angiocatheter. Ultrasound imaging was performed on the left hindlimb for three hours at five-minute intervals, and the average video intensity of the images was measured. Histological staining and immunohistochemistry were performed to validate the co-localization of microthrombi and RGD-AuNPs.

Results:
In the RGD-AuNPs+MVO group, enhanced ultrasound signals were visible at 15 minutes and progressively increased over three hours. The average video intensity in this group was approximately three times higher than that in the GSH-AuNPs+MVO group (11.88±3.68 vs. 3.39±2.67, p<0.001). No significant difference in average video intensity was observed between the GSH-AuNPs+MVO group and the GSH-AuNPs control group (3.39±2.67 vs. 3.50±2.09, p>0.05), or between the GSH-AuNPs control group and the RGD-AuNPs control group (3.50±2.09 vs. 2.95±2.18, p>0.05). Histological staining and immunohistochemistry confirmed the co-localization of microthrombi and RGD-AuNPs.

Conclusions:
Gold nanoparticles modified with the RGD peptide effectively enhance the signal of ultrasound imaging, enabling targeted imaging of thrombotic microvascular obstruction. This approach holds promise for improving the diagnosis and monitoring of MVO in clinical settings.
Abstract 18411: The Causal Association Between Coronary Artery Disease and Atrial Fibrillation in East Asian Ancestry
Authors: Wang Jingyang , Tan Jiangshan , Yang Yanmin
Published: December 2023

Background:
Previous studies have reported a causal association between coronary artery disease (CAD) and atrial fibrillation (AF) in the European populations. However, it is unclear whether the causal association the exists in East Asian populations.

Methods:
We assessed the causal relationship between CAD and AF using 2-sample Mendelian randomization (MR) in the East Asian populations. Additionally, we performed multivariable MR, correcting obesity, smoking initiation, alcohol intake frequency, and hypertension to further explore the causality between CAD and AF.

Results:
The calculated odds ratios (ORs) and 95% confidence intervals (CIs) for CAD using inverse-variance weighted, MR-Egger, and weighted-median analysis were 0.984 (0.955-1.014; P = 0.285), 0.957 (0.899-1.019; P = 0.191), and 0.974 (0.945-1.004; P = 0.088), respectively; for AF, the results were 1.066 (0.944-1.203; P = 0.302), 0.790 (0.546-1.142; P = 0.216), and 1.258 (1.098-1.441; P < 0.001). After adjusting common risk factors, the genetically predicted CAD was also causally associated with an 18.5% increased risk of AF (OR = 1.185; 95% CI = 1.065-1.319; P = 0.002), but no causal effect of AF on the risk of CAD.

Conclusions:
Our findings suggest that genetically predicted CAD is causally associated with an increased risk of AF in East Asian populations.
Abstract 18414: Risk of Stroke After Atrial Fibrillation Ablation in Patients Without Pre-Ablation Left Atrial Appendage Evaluation
Authors: Lee Kevin , Minga Iva , Varley Allyson , Thorne Christopher , Osorio Jose , Singleton Matthew J , Silverstein Joshua , Metzl Mark
Published: December 2023

Introduction:
Currently, transesophageal echocardiography (TEE), intracardiac echocardiography (ICE), or CT angiography (CTA) are often though not always performed to assess the left atrial appendage (LAA) prior to ablation to reduce the risk of stroke. We seek to evaluate in a large, real-world registry if rates of stroke are similar in patients who do not have this evaluation and are on at least three weeks of anticoagulation prior to ablation.

Methods:
The REAL-AF registry is a multicenter prospective registry that is enrolling patients undergoing AF ablation at high-volume centers. Data from a total of 2704 patients (mean age 66 ± 11 years, 42% female) receiving index ablation for paroxysmal and persistent AF were obtained and included in the analysis. The patients who suffered strokes within 12 months of ablation were analyzed.

Results:
A total of 1522 (56%) patients received TEE, 1143 (42%) received ICE, 153 (6%) received both TEE and ICE, 95 (4%) received CTA, and 97 (4%) did not received any evaluation for LAA clots pre-ablation. CHA
2
DS
2
VASc was significantly higher in the not screened group compared to the screened group ((3.18 [2.84 - 3.51]) vs 2.65 [2.59 - 2.71],
p
< 0.01). Three patients (0.1%) suffered strokes after ablation, two who had been screened by ICE, and one who had not been screened. No patients who were screened by TEE or CTA suffered strokes. All three patients with strokes were on therapeutic oral anticoagulation prior to ablation. The two patients screened with ICE had a CHA2DS2VASC of 2 and 7, while the patient without screening had a score of 6. Patients who were not screened had a statistically significant higher likelihood of having a stroke compared to those who received LAA screening with TEE, ICE, or CTA (OR = 13.2 [1.2 - 147],
p
= 0.04).

Conclusion:
While absolute rates of stroke after AF ablation are low, in our cohort occurring in only 0.1% of patients, there was a statistically significantly higher odds of developing stroke in patients who did not have their LAA screened prior to ablation.
Abstract 18418: Osteoprotegerin Mediates T-Cell Response in Myocardial Wound Healing Post-Ischemic Injury
Authors: Knight Thomas W , Wagner Marcus J , Megill Emily , Asangwe Ngefor , Kraus Lindsay , Kubo Hajime , Khan Mohsin , Mohsin Sadia
Published: December 2023

Introduction:
Myocardial Infarction (MI) triggers an inflammatory response associated with cardiac wound healing. T-regulatory cells (Tregs) play a crucial role in the MI heart during this inflammatory response via their regulation of cardiac repair and function. Stimulating and sustaining the pro-reparative T cell response after MI would aid in preserving cardiac structure and function. Cortical Bone derived Stem Cells (CBSCs) possess a diverse array of inflammatory signaling molecules that can influence the inflammatory microenvironment of the heart after MI. A paracrine factor, Osteoprotegerin (OPG), is abundantly present in CBSCs, but it is unknown if OPG can mediate Tregs in myocardial injury.

Hypothesis:
CBSCs-derived Osteoprotegerin can regulate cardiac wound healing post-MI by modulating T cell response.

Methods and Results:
T cells exposed to CBSC secretome underwent an upregulation of a Treg population (p≤0.0001) characterized by the expression of Tumor Necrosis Factor Receptor II (TNFRII). Further investigation into the CBSC secretome highlighted OPG as a potent signaling molecule responsible for inducing TNFRII+ Tregs (p≤0.0001) measured by FACS analysis. siRNA-mediated depletion of OPG studies showed compromised TNFRII+ Treg induction (p≤0.0001). In vivo studies, adult FoxP3-GFP (12-16 week) mice underwent left anterior descending artery ligation followed by intramyocardial injection of CBSCs, Mesenchymal Stem Cells (MSCs), or vehicle (saline) along the infarct border zone. Resident T-lymphocyte populations were assessed at 1- and 8-weeks post-MI via flow cytometry. CBSC-treated hearts yielded a greater prevalence of TNFRII+ Tregs at 1- and 8-weeks following MI compared to MSCs (p≤0.01; p≤0.0001) and vehicle (p≤0.0001; p≤0.05). CBSC induction following MI reduced infarct size compared to the vehicle (p≤0.05). Ablation of the Treg population in the ischemic zone following MI increased infarct size and solicited adverse cardiac remodeling (p≤0.05).

Conclusion:
Osteoprotegerin can promote cardiac wound healing by facilitating the expansion and preservation of pro-reparative TNFRII+ Tregs.
Abstract 18459: A Cell Permeable Protein Kinase C Beta II Peptide Inhibitor Mitigates the Generation of Reactive Oxygen Species in Rat ex-vivo and Porcine in-vivo Ischemia-Reperfusion Injury
Authors: Ramsarran James , Clair Logan , Melnik Juliet , Boakye Tanoh Desmond , Dang Jennifer , Augustin Taurai , Dean Tameka , CHEN Qian , Barsotti Robert , Young Lindon
Published: December 2023

Introduction:
Restoration of blood flow following myocardial infarction is necessary to salvage ischemic tissue, but reperfusion is known to cause myocardial ischemia/reperfusion injury (MIR). Cytokine induced translocation of protein kinase C beta II (PKCβII) during reperfusion (R) stimulates the production of reactive oxygen species (ROS). Dual conjugation of PKCβII peptide inhibitor (PKCβII-) with myristic acid (myr) and trans-activator of transcription (Tat) (myr-Tat-CC-SLNPEWNET [myr-Tat-PKCβII-]) enhances intracellular delivery and reduces phorbol ester-induced neutrophil ROS. We hypothesize that 20ng/kg of myr-Tat-PKCβII- would exert cardioprotective effects in porcine MIR in-vivo by reducing stimulation of ROS.

Methods:
Ex vivo:
We tested 100nM - 10fmol myr-Tat-PKCβII- in ex-vivo rat MIR. Isolated hearts from anesthetized male SD rats underwent global I (30-min)/R(50-min). Myr-Tat-PKCβII- was given during first 5min of R. DP/dt max was measured via pressure transducer in the left ventricle. 1% TTC staining was used to determine infarct size. Data was analyzed via Fisher’s PLSD.
In vivo:
Regional I (1 hr)/R (3 hrs) was induced in male Yorkshire pigs. At R, myr-Tat-PKCβII- or scrambled control peptide (20ng/kg; ~100 pM blood volume [vol.] concentration [conc.]) was given by intra-arterial bolus. Ejection fraction (EF) was calculated. Infarct size was determined with Evans Blue dye and 1% TTC staining. Data was analyzed using Student’s t-test.

Results:
Ex-vivo:
Myr-Tat-PKCβII- (100nM - 100fmol; 10-14±3%; n=3-6) significantly reduced infarct size compared to controls (21±3%; n=21; p<0.05). DP/dt max was significantly improved (100pM-1pM; 961±274; n=5-6) compared to 100nM (163±77, n=3; p<0.05), 100fM (481±86, n=5; p<0.05), and 100pMscrambled myr-Tat-PKCβII- (386±86, n=4; p<0.05).
In-vivo:
Myr-Tat-PKCβII- 20ng/kg (~100pM blood vol. conc.) significantly restored EF to within 1.4±0.7% of baseline and reduced infarct size to (10.0±2.8%; n=4) compared to control (6.4±2.1%; 28.5±8.3%; n=6; p<0.05).
Conclusions:
Results suggest 20ng/kg (~100pM blood vol. conc.)) should continue to be used to test in porcine MIR in-vivo. Future studies include a 12-week porcine survival study to evaluate infarct size and cardiac function.
Abstract 18472: Plasma Proteome Changes in Heart Failure and Non-Heart Failure Patients Undergoing Cardiac Surgery
Authors: Parikh Jhana , Foster Matthew , Ghadimi Kamrouz
Published: December 2023

Introduction:
Patients with and without heart failure display different clinical courses after cardiac surgery.

Hypothesis:
Unbiased analyses of the plasma proteome from extreme phenotypes in myocardial function may identify differences in candidate proteins differentially modified by cardiac surgery using cardiopulmonary bypass (CPB).

Methods:
We combined two prospectively-collected datasets: Left ventricular assist device (LVAD) recipients from the INSPIRE-FLO trial (N=94, NCT03081052) and coronary artery bypass graft (CABG) surgery patients with normal biventricular function (N=50). For each population, we obtained EDTA-plasma from arterial blood sampling in the operating room and on postoperative day 1. Including quality control pools, 304 total samples were digested in a 96-well format with trypsin. Peptides were analyzed by microflow liquid chromatography coupled to tandem mass spectrometry using data-independent acquisition. Proteins were identified and quantified at a 1% false discovery rate (FDR) in Spectronaut. Statistical analyses utilized a t-test with FDR correction (significance defined by log2FC>1 and q<0.05).

Results:
There were 943 protein groups quantified in at least one plasma sample. Patients undergoing LVAD surgery had significantly higher levels of 135 proteins including acute phase reactants (CRP, SAA1, SAA2), putative neutrophil-derived proteins (S100A8/9) and markers of renal insufficiency (B2M and REG3A) (Figure 1). Cardiac surgery using cardiopulmonary bypass increased acute phase and inflammatory markers, and cardiac proteins (ENOB, MYG and KCRM), with NGAL, TIMP1 and PAI1 among proteins with higher absolute increase after LVAD implantation versus CABG surgery (
Fig.1
).

Conclusions:
Unbiased analyses of the plasma proteome identifies baseline and postoperative differences associated with extreme phenotypes of myocardial function undergoing cardiac surgery using CPB.
Abstract 18509: NT-proBNP Trajectories and Heart Failure Risk Associations in Middle to Older Ages in Adulthood: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ozkan Bige , Pavlovic Noelle , Nambi Vijay , Echouffo Justin B , Jia Xiaoming , Ballantyne Christie M , Shah Amil M , Blumenthal Roger S , Matsushita Kuni , Selvin Elizabeth , Coresh Josef , Ndumele Chiadi E
Published: December 2023

Background:
NT-proBNP is a powerful marker of heart failure (HF) risk. NT-proBNP levels increase with age; however, the impact of distinct longitudinal trajectories of NT-proBNP on future HF risk with aging is largely unexplored.

Hypothesis:
Middle-aged adults with higher baseline concentrations and steeper increases of NT-proBNP through older ages have greater HF risk.

Methods:
We performed a prospective analysis of 12,124 ARIC participants with 2 or more serial NT-proBNP measurements from Visits 2 through 6, without HF at baseline or HF events between the NT-proBNP assessments. We constructed linear mixed models to evaluate NT-proBNP trajectories for males and females. We defined 4 trajectories, using sex-specific medians to define high versus low: low baseline/low slope, low baseline/high slope, high baseline/low slope, high baseline/high slope. We used Kaplan Meier survival curves and multivariable Cox regression to evaluate the HF risk associations of different NT-proBNP trajectories.

Results:
The mean age was 57 years with 56% women and 23% Black adults, BMI 27. The median baseline NT-proBNP concentrations were 62 and 36 pg/mL and the average NT-proBNP slopes were 4.6% and 7.2% increase/year for women and men, respectively. Black individuals were more likely to have lower baseline levels, whereas those with diabetes, obesity, or prevalent coronary heart disease had higher slopes. Over a median 22-year follow-up, 2,772 HF events occurred. There was a stepwise increase in HF risk with higher baseline levels and slopes of NT-proBNP, with individuals with the high baseline/high slope NT-proBNP trajectory having a HR for HF of 3.70 (95% CI 3.26-4.20) compared to those with low baseline-low slope (
Figure
).

Conclusions:
Higher baseline concentrations and steeper increases of NT-proBNP with aging are associated with greater HF risk. Identifying and addressing modifiable determinants of NT-proBNP trajectories with aging may have implications for HF prevention.
Abstract 18514: A Simulation Study on the Inducibility of Atrial Fibrillation Drivers From Intra-Atrial Electrode Catheters Using Personalized Computational Models Based on LGE-MRI
Authors: Sakata Kensuke , Yamamoto Alves Pinto Carolyna , Ali Syed Yusuf , Loeffler Shane , Tice Brock , Bradley Ryan P , Prakosa Adityo , Kholmovski Eugene G , Trayanova Natalia A
Published: December 2023

Introduction:
Although non-inducibility of atrial fibrillation (AF) drivers just after pulmonary vein isolation (PVI) with or without substrate ablation for persistent AF (PsAF) has been proposed as an acute outcome suggesting a successful long-term outcome, recent studies have found no association with long-term freedom from atrial tachyarrhythmias. It is unclear whether the latter finding is due to complete elimination of all AF drivers or the inadequacy of an AF induction test. Recently, patient-specific computer simulation based on late gadolinium enhancement (LGE)-MRI has been proposed to be useful for detecting rotors as PsAF drivers.

Hypothesis:
By investigating the accuracy of an induction test following PsAF ablation from the sites commonly used in clinical practice, particularly coronary sinus (CS), we might establish the promising method to confirm non-inducibility during ablation procedure.

Methods:
Thirty-five consecutive PsAF patients underwent LGE-MRI tests for fibrosis-based computational models. Rotors were induced by rapid pacing from 40 bi-atrial sites near fibrosis after PVI then ablated, repeated until obtaining non-inducibility of rotors. Each induced rotor was investigated for whether it was induced by pacing at lateral right atrium (RA), high RA or CS where electrode catheters were typically placed and used for induction test (Figure).

Results:
Except for 9 patients having poor LGE-MRI images or low fibrosis burden, 21 patients had a total of 136 locations capable of sustaining extra-PVI rotors. Of the total amount of rotors induced, 24% were induced by pacing at lateral RA, 11% at high RA and 45% at CS, respectively. The capture of all arrhythmogenic locations capable of sustaining rotors improved to 59% by performing induction test from all 3 pacing sites instead of a single one (p<0.01).

Conclusions:
Although CS is the reasonable pacing site for induction test, that from RA should be also conducted for the optimal rotor detection.
Abstract 18518: Exploring Sleep's Impact On Sex And Racial/ Ethnic Disparities In Cardiovascular Disease Risk: Leveraging Machine Learning And Precision Insights To Unravel Sleep-cvd Connections In 10-year Sleep Health Health Study
Authors: Rogers April , Chung Dr Debbie , Seixas Azizi A , Chung Alicia , Zizi Ferdinand , Jean Louis Girardin
Published: December 2023

Introduction:
The study aimed to explore the connection between insufficient sleep (<7 hrs.) and 10-year cardiovascular disease (CVD) risk levels in black and white individuals, using Framingham risk (FRS) and Reynolds risk (RRS) scores. It also sought to identify and characterize the CVD risk factors associated with heightened or reduced risk profiles.

Methods:
Using the Sleep Heart Health Study (SHHS) (N=6,441) data, we investigated the independent role of insufficient sleep in explaining differences in 10-years CVD between blacks and whites via a proportional odds model of four 10-year CVD risk groups: low (<5%), low-medium (5% to <10%), medium-high (10% to <20%) and high (≥20%), adjusting for age, sex, and apnea-hypopnea index (AHI). We performed two levels of cluster analyses; via hierarchical cluster algorithm with entire sample (Level 1), and latent profiles in the low (protective profiles) and high (risk profiles) CVD risk groups (Level 2) to determine overall CVD risk, and risk and protective CVD profiles.

Results:
Blacks had a higher prevalence of smoking behavior, diabetes, mean systolic blood pressure, body mass index, total cholesterol compared to whites. Conversely, whites had a higher mean HDL cholesterol, sleep hours, and sleep efficiency compared to blacks. Men had higher 10-year CVD risk than women. AHI and race/ethnicity-sleep interaction were positively associated, while sleep was negatively associated with FRS and RRS. Across all CVD risk groups, whites who slept less than 5.5 hrs. had a higher CVD risk and those who slept more than 6.5 hrs. had a lower CVD risk compared to blacks. In Level 1 cluster analyses, we found two clusters: Cluster 1 (n= 3233): 6.17 sleep hours, apnea-index 11.84, age 59, SBP 125.43, total cholesterol 209, HDL 51.39, BMI 29.03, and slightly more than 50% female; and Cluster 2 (n=1657): 5.61 sleep hours, apnea-index 13.41, age 74, SBP 131, total cholesterol 204, HDL 50.30, BMI 26.45, and slightly less than 50% female. In Level 2 cluster analyses, we found two profiles within the low and high CVD risk groups.

Conclusions:
These findings suggest that blacks may not receive full protection from long-term CVD risk with longer sleep duration, as their white counterparts.

Support: R01HL142066, R01AG067523, R01AG075007
Abstract 18532: Cardiomyopathy Diagnoses in a General Population Study of
TTN
Pathogenic Variants: A Missed Opportunity to Diagnose Familial Cardiomyopathy?
Authors: Knowlton Kirk U , Walton Nephi , Najarian Gabriel , Christensen G B , Evans Jared M , May Heidi T , Anderson Jeffrey L , Nadauld Lincoln , Knight Stacey
Published: December 2023

Introduction:
Intermountain Health’s HerediGene Population Study has been collecting samples from over 175,000 individuals since 2018 to identify those that could potentially benefit from early interventions. Variants in the
TTN
gene are the most common genetic causes of cardiomyopathy (CM). Here we examined all individuals with TTN pathogenic or likely pathogenic variants to determine differences in clinical characteristics among those with and without a clinical CM diagnosis (Dx).

Methods:
Whole genome sequence was analyzed in 32,159 individuals. 411 (1.3%) had a pathogenic/likely pathogenic
TTN
variant
.
Of these 135 (32.8%) had a CM Dx and 276, (67.2%) did not. Differences in health histories, ECHO results, treatments, and major CV events were evaluated by presence or absence of CM Dx using the chi-square, Fisher exact, and Wilcoxon rank sum tests.

Results:
Demographic and clinical characteristics were significantly different among those with and without a CM Dx (Table). In those without CM Dx, a total of 75 (27%) had some clinical indication of potential CM: 37 having a BNP ≥100, 7 had an LVIDd ≥ 5.5, 33 with an EF ≤55%, 3 experiencing cardiac arrest, and 45 with a heart failure Dx. Of these, 21 (28%) had 2 of these indications, 13 (17%) had 3 indications, and 1 (1%) had 4 indications. Among these with indication of CM without a Dx, 12 (16%) have died, and 22 (23%) have been hospitalized for heart failure. Only 8 individuals had a clinical genetic test for CM with a positive result for
TTN
variant.

Conclusion:
About 1/3 of potential pathogenic
TTN
variant carriers had a CM Dx and 27% without a CM Dx had indication of possible CM. A small percentage of
TTN
variant carriers with a CM Dx and none of those with possible CM have undergone clinical genetic testing. This demonstrates a missed opportunity to diagnose potential
TTN
-related familial CM for earlier intervention and treatment of patients and family members.
Abstract 18539: The Impact of Prophylactic Heparin on Pocket Hematoma Formation After Cardiac Implantable Electronic Device Implantation a Real-World Experience
Authors: Patel Harsh P , Peters Garrett , Kumar Ashish , Agarwal Siddharth , Mazimba Sula , Deshmukh Abhishek , Mehta Nishaki M
Published: December 2023

Introduction:
Intravenous heparin is strongly associated with pocket hematoma (PH) formation in patients undergoing cardiac implantable electronic device (CIED) implantation. However, there is no data on subcutaneous prophylactic heparin in this population

Hypothesis:
We hypothesized that the subcutaneous heparin may increase the odds of PH in patients undergoing CIED implantation using data from a large, nationally representative sample of the US population.

Methods:
The Premier Healthcare Database was analyzed from 2016-2019 to identify patients >18 years old undergoing CIED implantation. Patients with PH were then identified by using ICD-10 CM codes. A multivariable logistic regression model was used to adjust for confounders

Results:
A total of 267,650 patients underwent CIED implantation between January 1, 2016, and December 31, 2019, of which 4,496 (1.68%) \developed PH. Single chamber pacemaker in 7.22%, dual-chamber pacemaker was implanted in 58.3% of patients, and CRT-P in 4.59%, ICD in 18.58%, CRT-D in 11.31%. Of the total cohort, 559 Patients received subcutaneous heparin within 3 days of the CIED implant procedure. Of these 559 patients, 91 (16%) patients were on subcutaneous heparin (pre-procedural: 19; post-procedural: 57) and developed PH. Subcutaneous heparin is associated with increased odds (OR :13.8,p<0.01) of PH formation.

Conclusions:
This study suggests that subcutaneous heparin is a strong risk factor for the development of PH. This may independently drive up the rates of PH in the inpatient population. Further studies on the timing of subcutaneous heparin need to be conducted.
Abstract 18545: GSK-3β Prevents Lipotoxicity in Obesity Cardiomyopathy Through Upregulation of ATGL
Authors: Takayama Koichiro , Nakada Yasuki , Maejima Yasuhiro , Sadoshima Junichi
Published: December 2023

Introduction:
Obesity induces accumulation of lipids in cardiomyocytes, leading to cardiac dysfunction, termed lipotoxic cardiomyopathy. We have shown previously that GSK-3α promotes fatty acid uptake in the heart. In contrast, GSK-3β may mediate lipid catabolism. In this study, we aimed to elucidate the role of GSK-3β in lipolysis, primarily focusing on the post-translational regulation of FoxO1 and its association with ATGL, which is the first lipase to hydrolyze lipids.

Methods:
Wild-type (WT) and homozygous cardiac-specific GSK-3β knock-out (GSK-3β-cKO) mice were fed a normal diet (ND) or a high fat diet (HFD) for 3 months.

Results:
HFD consumption in WT mice activated GSK-3β in the heart, as indicated by decreases in Ser9-phosphorylated GSK-3β/total GSK-3β (0.5-fold, p<0.05 compared to ND consumption), and upregulated ATGL (2.4-fold, p<0.05) in the heart. Echocardiographic analyses showed preserved systolic and diastolic function in WT mice at this time point (LVEF: 56.3 ± 1.5 %, E/A: 2.06 ± 0.22, n = 13). However, ATGL was not increased (1.6-fold) and both systolic and diastolic dysfunction were observed (LVEF: 45.8 ± 1.5 %, p<0.01 compared to WT, E/A: 1.43 ± 0.20, p<0.05, n =12) in GSK-3β-cKO mice fed a HFD. GSK-3β overexpression in neonatal rat ventricular cardiomyocytes increased ATGL in a dose-dependent manner (p<0.05). FoxO1 knock-down on this background inhibited upregulation of ATGL, suggesting that GSK-3β-induced upregulation of ATGL is mediated through a FoxO1-dependent mechanism. Immunoprecipitation showed that GSK-3β interacts with FoxO1, while mass spectrometry analyses revealed that GSK-3β phosphorylates FoxO1 at 8 Serine/Threonine residues. A FoxO1 mutant in which Serine/Threonine residues at the GSK-3β phosphorylation sites are mutated to Alanine was excluded from the nucleus, and its overexpression prevented upregulation of ATGL in the presence of GSK-3β overexpression.

Conclusions:
GSK-3β is activated in the presence of HFD consumption in the heart, which may, in turn, prevent lipotoxic cardiomyopathy through phosphorylation of FoxO1 and upregulation of ATGL.
Abstract 18548: Racial Disparities in the In-Hospital Outcomes of Patients Undergoing Percutaneous Peripheral Endovascular Procedures
Authors: Orji Richard , Nso Nso , Markson Favour , Ilelaboye Ayodeji , Harb Ahmad , Salah Abdelraouf , Nwaedozie Somto
Published: December 2023

Introduction:
Endovascular revascularization is becoming the mainstay management of peripheral vascular disease (PVD). Our study seeks to find out the impact of racial disparity on the outcome of this procedure.

Methods:
We queried the National Inpatient Sample (NIS) database from 2016 to 2019. The NIS is the largest all-payer inpatient healthcare database in the United States. The NIS was searched for hospitalization of adult patients with PVD who had endovascular revascularization, using the International Classification of Diseases, Tenth Revision (ICD-10) codes. Following Propensity score matching, we assessed for a primary outcome of inpatient mortality. The secondary results were acute kidney injury (AKI), amputation, cardiac arrest, cardiogenic shock, total hospital charge (THC), and length of stay (LOS).

Results:
About 395,510 patients with PVD had endovascular revascularization; 322,015 patients who had the procedure were either White (n=254,840, 79.1%) or Black (n=67,175, 20.9%). White patients had a mean age of 69.2±0.1 years compared to 64.9±0.1 years in Black patients (males: 61.1% versus 53.4%; females: 38.9% versus 46.6%). Compared to White patients, Blacks had significantly lower in-hospital mortality (2.2% versus 2.6%; p=0.005) and cardiogenic shock (0.9% vs 1.2%; p=0.004); however, they had significantly higher AKI (21.6% vs 19.0% p-value 0.015), amputations (7.6% vs 4.4% p-value <0.001), and LOS (10.1 vs 7.5; p-value <0.001) compared to Whites.

Conclusions:
This study showed that compared to Whites, Black patients were more predisposed to amputations, AKI, and higher LOS despite having a lower mortality rate after endovascular revascularization.
Abstract 18550: Impaired Microtubule Mediated Protein Trafficking as a Mechanism of PLN R14del Dilated Cardiomyopathy
Authors: Baum Rachel , Ramchandani Rohin , Karakikes Ioannis , Arthur Jennifer , Bharucha Nike , Dunkenberger Logan
Published: December 2023

Introduction:
Phospholamban (PLN) regulates calcium handling and contractility in the heart by altering its phosphorylation status, thereby activating or inhibiting the calcium ATPase SERCA2a. A pathogenic mutation in PLN at the Arginine 14 codon (R14del) results in dilated cardiomyopathy characterized by ventricular arrythmias and sudden cardiac death. Cytoplasmic aggregation of PLN is a hallmark of the disease. However, exactly how the R14del mutation causes DCM remains largely unknown. As PLN is trafficked to the cell membrane before it localizes to the t-tubules, we hypothesize that PLN protein trafficking may be impaired, contributing to the PLN aggregation and DCM.

Methods:
Induced pluripotent stem cell derived cardiomyocytes (iPSC- iPSC-CMs) from patients carrying the PLN R14del mutation and isogenic controls generated by CRISPR-Cas9 genome editing were tagged with biotin to quantify membrane-bound protein expression. Western blotting and mass spectrometry was used to identify differences membrane protein expression, and immunocytochemistry was used to image microtubule layout, PLN and junctional protein expression at the cell borderintercalated disc (do you mean the intercalated disk?) in micropatterned iPSC-CMs.

Results:
Quantification of membrane-bound proteins showed a significant decrease of PLN at the cell membrane and connexin 43 expression in the intercalated disk of R14del iPSC-CMs compared to isogenic controls. Additionally, we observed significantly reduced levels of EB1, the microtubule tip protein, at the cell border of PLN R14del iPSC-CMs by immunofluorescence imaging and western blot analysis. Finally, disruption of microtube polymerization by Nocodazole treatment, induced PLN aggregate formation in iPSC-CMs.

Conclusion:
Our data suggest that the transportation of PLN and Cx43 proteins by microtubules is impaired in PLN R14del iPSC-CMs, which results in PLN accumulation in the cytoplasm and a decrease of Cx43 expression in the intercalated disc. These findings provide a novel mechanism for the pathogenesis of PLN R14del cardiomyopathy and a possible therapeutic target.
Abstract 18558: Modeling Cardiac Amyloidosis: Insights Into Pathogenesis and Therapeutic Strategies
Authors: Glatstein Shany , Arbel Gil , Huber Irit , wexler yehuda , Ghiringhelli Matteo , Gepstein Lior
Published: December 2023

Introduction:
Cardiac transthyretin (TTR) amyloidosis is an underdiagnosed cause of heart failure and cardiac arrhythmias. The lack of relevant human cardiac tissue models hinders understanding of the underlying mechanisms and development of effective treatments.

Hypothesis:
We aimed to establish an in vitro model of cardiac amyloidosis using human-induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) and aggregated TTR and investigate cellular changes and potential therapeutic targets.

Methods:
Wild-type and mutated TTR proteins were aggregated and added to hiPSC-CM cultures directly or embedded in Matrigel used for culture-plate coating. Single-cell and two- and three-dimensional hiPSC-CM models were used for real-time microscopy, calcium and voltage imaging, immunostaining, apoptosis, ROS assays, and proteomics studies with mass spectrometry.

Results:
Immunohistochemical and histological staining confirmed the deposition of TTR aggregates within the hiPSC-CM tissue models. Cells exposed to TTR aggregates exhibited increased apoptosis and increased production of reactive oxygen species (ROS). TTR-treated cells also displayed irregular calcium transients, characterized by oscillating calcium peaks and double-humped signals. The presence of TTR also induced morphological changes, including cell shrinkage at the single-cell level and the formation of holes in 2D hiPSC-CM cell sheets due to cell migration and apoptosis. These holes led to conduction abnormalities and the development of reentrant arrhythmias, specifically spiral waves. The severity of these abnormalities was markedly increased when mutant TTR aggregates were used. Proteomics studies suggest a potential involvement of the mTOR signaling pathway in the pathogenesis of cardiac amyloidosis.

Conclusions:
Our in vitro model successfully recapitulated key features of cardiac amyloidosis and revealed significant protein expression changes. These findings provide valuable insights into disease pathogenesis and potential therapeutic targets and highlight the utility of our model for studying cardiac amyloidosis for the development and evaluation of novel therapeutic strategies.
Abstract 18560: External Calcium Modification Technique to Recanalize a Balloon Uncrossable Chronic Coronary Total Occlusion
Authors: Hashemi Arash , Hashemi Ashkan , Shah Meet
Published: December 2023

Introduction:
Despite improvements in equipment and techniques, uncrossable chronic total occlusion (CTO) coronary lesions remain challenging.Case: A 66-year-old male with typical angina and a history of failed CTO PCI was referred to our CTO tertiary center as he did not wish to undergo coronary artery bypass grafting. Transthoracic echocardiography revealed an ejection fraction of 45%, and cardiac MRI demonstrated viability in the LAD region. Coronary angiography revealed a long LAD CTO over 20 mm with heavy calcification (Figure 1a). The J-CTO score was calculated to be 4. The cap of the CTO was semi-ambiguous. The wire was advanced through the highly calcified lesion with the support of a microcatheter but the microcatheter and low-profile balloons were unable to be advanced despite backup with 7 French femoral access and an EBU catheter in place (Figure 1b) Upon failure on using Leopard crawl technique and grenadoplasty and with unfavorable side branch anatomy for STAR technique, cracking the calcification with a balloon advanced over a subintimal hydrophilic wire was considered. A fielder XT-A guidewire was advanced around the CTO lesion in the subintimal area (Figure 1c). A 2x12 mm balloon was inflated at 8 atm over the wire situated in the subintimal area in order the crack the calcification from outside. After extraluminal plaque modification, the wire and the balloon were withdrawn. A microcatheter was then able to be advanced with the support of an anchor balloon over the original true lumen wire (Figure 1d). Then the procedure was successfully completed with balloon dilatation and stent implantation (Figure 1e-f).

Conclusion:
External Calcium Modification technique which consists of plaque modification using a balloon in subintimal space (over an intentionally directed wire in subintima and around the calcium) and cracking the calcium from the outer vessel structure can be used as a last resort to overcome balloon uncrossable CTO lesions.
Abstract 18563: Unraveling the Interplay Between Age, Obesity, and Mortality Across Adulthood: Insights From National Health and Nutrition Examination Survey 1999-2018
Authors: Lu Yuan , Mou Yunhan , Liu Yuntian , Herrin Jeph , Krumholz Harlan M
Published: December 2023

Introduction:
Obesity is a major public health concern in the US, but the specific effects on mortality by age remain unclear. This study examined the complex relationship between age, obesity, and mortality.

Methods:
We analyzed data from the National Health and Nutrition Examination Survey (1999-2018) and linked mortality of adults aged 18 to 80 years. We examined interactions between age and obesity measures (body mass index [BMI], waist circumference, and weight) in relation to all-cause and cardiovascular mortality using Cox regression models.

Results:
The study included 44,041 adults (mean age: 44.8; SD=16.2). Among them, 50.5% were female, 12.2% were Black, 72.4% were White, and 15.4% were Hispanic. Significant age-obesity interactions were observed for all-cause and cardiovascular-specific mortality (P<0.01). Younger individuals had a higher hazard ratio (HR) for all-cause mortality per one SD increase in BMI (Age < 50, HR: 1.18, 95% CI: [1.06, 1.30]) and (Age 50-70, HR: 1.07 [1.00, 1.15]) compared with older individuals (Age > 70, HR: 0.98, 0.90, 1.06]), after adjusting for covariates including sex, race/ethnicity, education, income, health insurance, physical activity, and smoking. Similar patterns were observed for all obesity measures, all-cause and cardiovascular mortality. Being underweight had a greater impact on risk in younger individuals compared with older individuals.

Conclusions:
Our findings indicate significant age-obesity interactions for all-cause and cardiovascular mortality. Younger individuals who were overweight or underweight faced a higher risk of mortality compared with older individuals.
Abstract 18578: BMP9 Regulates Endothelial Expression of Mediators of Pulmonary Vascular Remodeling
Authors: Zhong Ying , Troncone Luca , Convington Taylor , Yang Peiran B , Worst Lillian R , Rajesh Shreyas , Zeghibe Ana , Shin Elizabeth , McNeil Megan , Kim Stephanie S , Bocobo Geoffrey A D , Szulcek Robert , Bogaard Harm J , Yu Paul B
Published: December 2023

Background:
Loss-of-function mutations in
GDF2
/BMP9 are found in heritable pulmonary arterial hypertension (PAH), suggesting a protective role, while protective or pathogenic effects are found in experimental PAH studies depending on context. The net contribution of BMP9 in PAH thus remains controversial.

Hypothesis:
BMP9 regulates the secretome of pulmonary microvascular endothelium (PMVEC) to contribute to pulmonary artery smooth muscle cell (PASMC) phenotype modulation.

Methods:
We tested recombinant BMP9, BMP9/BMP10 trap ALK1-Fc, and BMP9 neutralizing antibody before and after development of pulmonary hypertension (PH) in distinct experimental models. We analyzed the impact of BMP9 on the PMVEC transcriptome, intersection with human and experimental PAH lung transcriptomes, and tested the impact of EC-derived genes on PASMC phenotype and growth.

Results:
ALK1-Fc and anti-BMP9 prevented or reversed experimental PH administered before or after onset of experimental PH. Recombinant disulfide-linked BMP9 was not protective in SUGEN/Hypoxia (SU-Hx)- or monocrotaline (MCT)-induced experimental PH, in contrast to previous studies using incompletely disulfide-linked BMP9, suggesting dissociated monomers might function as competitive BMP9 antagonists. Consistent with this interpretation, BMP9 upregulated PMVEC genes associated with pulmonary vascular remodeling in experimental and human PAH including CXCL12, IGFBP4, ET-1, VEGF-A, and PDGF-BB. Stimulation of PMVEC with BMP9 induced a contractile phenotype (
CNN1;TAGLN
) in co-cultured PASMC. Administration of ALK1-Fc or anti-BMP9 attenuated expression of several of these growth factors in SU-Hx PH. In experimental PH ALK1-Fc and ACTRIIA-Fc elicited peripheral edema, a phenotype associated with use of ALK1-Fc in human trials.

Conclusions:
BMP9 contributes to experimental PH by regulating expression of EC-derived molecules modulating PASMC growth and phenotype. In contrast to broad strategies that inhibit BMP9 and BMP10 associated with HHT mimicry in clinical trials and rodent PH models, treatment with anti-BMP9 was well-tolerated. Selective antagonism of BMP9 represents a potential therapeutic strategy for human PAH.
Abstract 18587: Factors Associated With Changes in High Sensitivity Troponin and NT-proBNP in Response to Intensive Blood Pressure Lowering in SPRINT
Authors: Nguyen Thomas T , Varghese Achsah , Dalmacy Djhenne , Ascher Simon , Ballantyne Christie M , NAMBI VIJAY , de Lemos James A , Berry Jarett D
Published: December 2023

Background
We have recently shown that intensive SBP lowering was associated with a modest increase in hscTnT and a decrease in NT-proBNP. In the present study, we sought to compare the independent determinants of changes in biomarkers in intensive vs. standard SBP lowering in SPRINT.

Methods:
Hs-cTnT and NT- proBNP were measured at baseline, 1-year, and 2-year from stored specimens. Biomarker changes were analyzed according to categories (≥50% increase, ≥50% decrease, and <50% change). The impact of intensive SBP lowering on changes in biomarkers levels was assessed using multivariable-adjusted multinomial logistic regression models in standard and intensive SBP lowering separately.

Results:
Of 9,361 SPRINT participants, we measured cTnT and NT-proBNP in 8,828 (baseline), 7,887 (year 1), and 7,463 (year 2) free of CVD events. Among individuals with detectable hscTnT at baseline (≥6 ng/L), a 50% increase in hscTnT was observed in 4.5% (year 1) and 6.7% (year 2). Among individuals with baseline NT-proBNP ≥125 pg/mL, a 50% increase in NT-proBNP was observed in 16.7% (year 1) and 21.1% (year 2). Overall, a similar pattern of associations was observed with both biomarkers across treatment groups (see Figure). Several exceptions were noted. Prevalent CVD was associated with an increase in both NT-proBNP and hscTnT in the standard SBP lowering arm but not in the intensive SBP lowering arm. Higher baseline hscTnT was associated with an increase in hscTnT only in the standard arm. Furthermore, we observed biomarker-specific differences. For example, white race, female sex, and blood pressure were consistently associated with an increase in NT-proBNP. In contrast, declining renal function and male sex were associated with increasing hscTnT.

Conclusion
Factors associated with changes in biomarkers varied by treatment assignment and between biomarkers. These findings highlight the role of noncardiac factors on biomarker changes in the context of intensive SBP lowering.
Abstract 18591: Can the Clip Restore the Physiological Annular Morphology? Serial Quantitative 4d Echocardiographic Analysis
Authors: Kimura Toshiyuki , Watanabe Nozomi , Shibata Yoshisato
Published: December 2023

Background:
We sought to seek an answer for the question whether the transcatheter mitral valve edge-to-edge repair (TEER) without annuloplasty can induce chronic positive remodeling of the annulus and restore the physiological saddle-shape morphology after the procedure.

Methods:
We serially analyzed the 3D echocardiographic images in 20 patients who were successfully treated with MitraClip for symptomatic severe mitral regurgitation (MR) (16 functional, and 8 degenerative). Four patients who had the recurrence of MR greater than moderate at chronic phase (3 functional, and 1 degenerative) were also evaluated. 4D-volumetric transesophageal (TEE) and transthoracic echocardiography (TTE) data were assessed offline by dedicated software at 1) before, 2) 5-day and 3) 1-year after the clipping procedure.

Results:
Annulus shortened in anterior-posterior (AP) direction in early after the TEER procedure (5-day), with keeping anterolateral-posteromedial (AL-PM) diameter and annulus circumference. Following the initial A-P reshape of the annulus, annular diameters reduced both in AP and ML directions with restoring physiological saddle shape (annulus height/AL-PM diameter) in one-year after the valve leaflet intervention (see figure).

Conclusions:
Fixing leaflet coaptation by successful TEER could induce chronic positive remodeling of the entire mitral annulus, with restoring its physiological saddle shape. Our results show that simple reduction in MR burden can cause the beneficial restoration of the valve apparatus morphology. Progressive negative annular remodeling was found in patients with recurrent MR.