bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11504: Elevated Seismocardiography-Derived Chest Energy is Associated With Aortic Flow Abnormalities in Patients With Aortic Valve Disease
Authors: Johnson Ethan M , Barker Alexander J , Robinson Joshua D , Rigsby Cynthia K , Markl Michael
Published: June 2023

Introduction:
Aortic valve disease (AVD) can induce abnormal flow and elevated peak velocity (Vmax), which has known association with aortopathy and implications for intervention, and thus is a key metric in AVD management. Seismocardiogram (SCG) chest acceleration measurements have been shown indicative of AVD. This study investigated relations between SCG energy and established aortic flow measures.

Hypothesis:
We hypothesize that standard of care clinical Vmax measurements from echocardiography or MRI correlate with SCG chest acceleration energy metrics.

Methods:
Healthy controls and AVD patients received standard of care echo or MRI and a same day SCG measurement (image, A). Patients had tricuspid or bicuspid aortic valve (TAV, BAV) and were presenting for routine imaging to assess valve/flow function (image, B). Controls (no known cardiovascular disease) were prospectively recruited. Subjects gave informed consent with IRB approval. MRI included 4D flow (1.5T, 1-3mm³/30-40ms); echo included 2D Doppler imaging (1.7-3.3MHz, 12-40 FPS). Standardized ascending aorta (AAo) Vmax measurements were taken from MR or echo images. SCG energy was calculated by spectral decomposition.

Results:
Enrolment was 76 subjects: 52 controls (48±17.4y, 23 F), 24 patients (18 BAV, 6 TAV, 31±20.9y, 5 F). Patients had elevated peak velocities (227±103cm/s vs. 106±21cm/s, p<0.01) and elevated SCG energy (10.4±2.6dB vs. 8.3±1.4dB, p<0.01). A significant relationship between elevated AAo Vmax and increased SCG energy was observed (R=0.63, p<0.01) (image, C).

Conclusions:
Evaluation of SCG in context of AVD shows its potential utility to screen for valve mediated aortic flow changes. Correlation observed between SCG energy and peak velocities, a key metric for management of valve disease and aortopathy, indicates the relevance of SCG measurements in this context. These results show potential for use of SCG as simple, cost-effective front-line screening tool for AVD patients.
Abstract 11518: Incidence of Peripheral Arterial Disease in Patients With Coronary Artery Disease Following Cardiac Catheterization: A Prospective Observational Study
Authors: Sunner Sanjot , Welsh Robert C , Bainey Kevin R
Published: June 2023

Introduction:
Peripheral arterial disease (PAD) is a common vascular condition affecting roughly 800,000 Canadians annually with up to 50% being asymptomatic. As such, PAD is underdiagnosed and undertreated, despite being an independent predictor of cardiovascular (CV) risk. Moreover, PAD is commonly seen in patients with coronary artery disease (CAD) due to their shared atherosclerotic pathophysiology. Our aim was to gain a better understanding of the incidence and symptomatology of PAD in patients with established CAD on coronary angiography.

Methods:
Prospective subjects with CAD demonstrated on coronary angiography were immediately screened for PAD at the Mazankowski Alberta Heart Institute Cardiac Catheterization Laboratory. Following consent, a bedside ankle-brachial-index (ABI) (Microlife WatchBP Office ABI) was performed and the Edinburgh Claudication Questionnaire (ECQ) (validated for PAD) was administered. PAD was defined as an ABI≤0.90.

Results:
We recruited 100 patients (67.5 age ± 9.5 years, 18.0% female) between June 2021 to April 2022. Eighteen subjects (18.0%) had PAD as demonstrated by an abnormal ABI. In those with diabetes (n=34), PAD was more frequent (26.5% vs. 14.1%, p=0.068). Kappa agreement between ECQ and ABI was 0.32.

Conclusions:
In a prospective cohort of angiographically confirmed CAD patients, one-quarter had ABI confirmed PAD (even more common in diabetics). The ECQ provided modest agreement with ABI suggesting many of these subjects are asymptomatic. ABI can be used as a simple non-invasive tool at the bedside following cardiac catheterization to screen for PAD which has implications on subsequent guideline-directed medical therapy.
Abstract 11526: Voltage Gated Sodium Channel β1 Subunit Mimetic Peptide PS2L Increases Regulated Intramembrane Proteolysis of SCN1B/β1
Authors: Williams Zachary , Hoagland Daniel , Jourdan Jane , Gourdie Robert G
Published: June 2023

Clinical treatment for cardiac arrhythmias based on targeting ion channels is limited and can have deadly side effects. We previously reported that acute administration of SCN1B mimetic peptide βadp1 resulted in decreased action potential conduction velocity and increased arrhythmias in isolated guinea pig hearts. These changes were associated with disruption of trans-homophilic adhesion of the β1 subunit within gap junction-adjacent perinexal domains in intercalated discs.Following a strategy reported by two other independent groups working on intercellular adhesion molecules containing Ig domains, N-cadherin and desmoglein-2, we dimerized a c-terminal βadp1 sequence resulting in the peptide PS2L.Using Electric Cell-Substrate Impedance Sensing (ECIS) with Chinese Hamster 1610 cells stably expressing β1, we found that PS2L increases β1 mediated adhesion not only acutely, but unexpectedly for over 48 hours post-treatment. Regulated Intramembrane Proteolysis (RIP) of β1 sequentially by BACE-1 and γ-secretase results in a cleaved intracellular fragment that translocates to the nucleus and alters transcription of various genes, including VGSC subunits. Therefore, we hypothesized the long-term gain-of-adhesion-function with PS2L treatment resulted from increased RIP of β1, with downstream VGSC gene expression effects. Inhibition of γ-secretase with DAPT accumulates a C-terminal fragment (CTF) of β1 during RIP, enabling quantification of changes to RIP. Thus, 1610β1 cells were treated with 50μM PS2L, 1μM DAPT, 50μM PS2L+1μM DAPT or 0.1% DMSO control. Cells were fixed for β1 immunofluorescence (IF) or lysate was collected at 6-, 24-, and 48-hours post treatments for Western blotting.IF showed an increase in abundance of β1 48 hours after βadp1 treatment compared to DMSO, especially at cell borders. DAPT treatment significantly increased CTF levels compared to control at all timepoints (p<.0001). However, PS2L+DAPT treatment resulted in greater accumulation of β1 CTF levels over DAPT alone at the 6-hour timepoint but not later. (n=3, p<.05) In sum, our data indicates that PS2L may upregulate RIP of β1 with potential downstream effects on gene transcription of VGSC subunits, suggesting a path to a novel class of antiarrhythmics.
Abstract 11527: Regional Variation in Cardiovascular Genes Enables a Tractable Genome Editing Strategy
Authors: Krysov Vikki A , Wilson Rachel H , Ten Nicholas S , Youlton Nathan , De Jong Hannah N , Sutton Shirley , Huang Yong , Reuter Chloe , Grove Megan E , Wheeler Matthew T , Ashley Euan A , Parikh Victoria N
Published: June 2023

Recent rise in the number and therapeutic potential of genome engineering technologies has generated excitement in cardiovascular genetics. One significant barrier to their implementation is costly and time consuming reagent development for novel unique variants. Prior data have illuminated the potential for regional clustering of disease-causing genetic variants in known and potential novel functional protein domains. We hypothesized that most cardiovascular disease-relevant genes in ClinVar would display regional variant clustering, and that multiple variants within a regional hotspot could be targeted with limited prime editing reagents. We collated 2,471 high confidence pathogenic or likely pathogenic (P/LP) missense and truncating variants from 111 cardiovascular disease genes. We then defined a regional clustering index (RCI), the percent of P/LP variants in a given gene located within a pre-specified window around each variant. At a window size commensurate with maximally reported prime editing extension length, 78bp, we found that missense variants displayed a higher mean RCI than truncating variants. We next identified genes particularly attractive for pathogenic hotspot-targeted prime editing with at least 20 P/LP variants and observed that the mean RCI in missense variants remained higher than for truncating variants and for rare variants observed in the same genes in gnomAD (Mean±SD RCI
78bp
: P/LP ClinVar Missense=5.2±5.9%; P/LP ClinVar Truncating=2.1±3.2%, gnomAD Missense=2±3.2%, gnomAD Truncating=1.1±2.4%. p<2.2e-16; ANOVA with post hoc Bonferroni correction). Further, we tested the feasibility of prime editing for multiple variants in a single hotspot in KCNH2, a gene with a high mean missense variant RCI. Sixty variants were induced in this hotspot in HEK293 cells with CRISPR-X. Correction of these variants was attempted with prime editing using two overlapping prime editing guide RNA extensions. The mean prime editing efficiency across CRISPR-X-enriched variants within this hotspot was 57±27%, including 3 P/LP variants. These data underscore the utility of pathogenic variant hotspots in the diagnosis and treatment of inherited cardiovascular disease.
Abstract 11544: Prognostic Risk Stratification of Cardiac Metastasis via Quantitative Perfusion Cardiac Magnetic Resonance Imaging
Authors: Park Christine , Ruiz Maya Tania , Tak Katherine , Kim Jiwon , Steingart Richard , Weinsaft Jonathan W , Chan Angel T
Published: June 2023

Introduction:
Cardiac magnetic resonance (CMR) is widely used to assess cardiac masses, including cardiac metastases (C
MET
). Perfusion CMR can quantify magnitude of tumor vascularity; prognostic relevance of lesion perfusion among patients (pts) with C
MET
is unknown.

Methods:
The population comprised adult cancer pts with C
MET
and controls matched for cancer type/stage. Late gadolinium enhancement (LGE) CMR was the reference for C
MET
. Perfusion CMR quantified vascularity within lesions, including contrast enhancement (CER: maximum vs. baseline) and uptake (CUR [slope] ratios during gadolinium infusion (0.1mmol/kg). Follow-up was performed for mortality.

Results:
155 C
MET
pts (59 ± 15yo, 56% male) and cancer matched controls underwent CMR, including a range of primary cancers (sarcoma 22%, GU 17%, GI & lung 12%). Anti-cancer treatment, cardiac risk factors and LVEF were similar between groups (p=NS). In relation to LGE-CMR, perfusion yielded good performance to distinguish C
MET
(AUC 0.57-0.97; p < 0.001). During follow-up, C
MET
pts tended to have higher aggregate 1 year mortality vs. controls (56% vs. 46%; p=0.09); median time to death was 6.8 (2.5, 17.1) months post-CMR. Pts with C
MET
on perfusion CMR had higher mortality risk than controls (HR 1.41 [1.04-1.92], p=0.03), paralleling LGE-CMR (HR 1.52 [CI 1.14-2.02], p=0.004). C
MET
mortality increased stepwise with impaired perfusion (Figure A) and was highest among pts in the bottom (vs. top) CER tertile, corresponding to decreased tumor vascularity. Among cancer matched subgroups, pts with C
MET
in the bottom CER tertile had higher mortality than controls (p < 0.001); prognosis was equivalent to controls (p=NS) among pts with lesions in the highest two CER tertiles (Figure B).

Conclusions:
Perfusion CMR identifies CMET based on vascularity and stratifies prognosis: Among cancer pts with CMET on LGE, mortality increases in proportion to magnitude of decreased tumor vascularity on perfusion CMR.
Abstract 11556: Sodium/Glucose Co-Transporter 2 Inhibition and Attenuation of the Action Potential Duration in Patient-Specific Re-Engineered Heart Cells With Congenital Long QT Syndrome
Authors: Zhou Wei , Kim Maengjo , Tester David J , Giudicessi John , Ackerman Michael J
Published: June 2023

Background:
Long QT syndrome (LQTS) stems from cardiac action potential duration (APD) prolonging pathogenic variants in
KCNQ1
(LQT1),
KCNH2
(LQT2), or
SCN5A
(LQT3). Sodium/glucose co-transporter 2 inhibitor (SGLT2i), a class of drugs used to treat type II diabetes and all forms of heart failure, reduces cardiac late sodium channel current.

Objective:
To test the ability of three commercially available SGLT2i to reduce APD in patient-specific induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) models of LQT1, LQT2, and LQT3.

Method:
Patient-specific iPSC-CMs and a CRISPR/Cas9 gene-edited variant corrected, isogenic control (IC) iPSC-CMs were generated. The variant-corrected IC was used to determine the curative APD in order to establish the degree of APD attenuation. The SCN5A-P1332L (LQT3) and IC iPSC-CMs were tested with 10 μM of either canagliflozin (CANA), dapagliflozin (DAPA), or empagliflozin (EMPA). An ATXII (5μM)-induced APD prolongation iPSC-CM model, mimicking drug-induced LQT3, was also treated. The APD was measured 30 minutes, 1 hour, and 2 hours after treatment using local extracellular action potential recordings on multielectrode array. The efficacy of these SGLT2i were also tested in KCNQ1-V254M (LQT1) and KCNH2-G604S (LQT2) iPSC-CMs.

Results:
The APD90 was prolonged in SCN5A-P1332L iPSC-CMs compared to its IC (469 ± 4 ms vs 305 ± 2 ms, p<0.0001). While 10 μM of SGLT2i had no APD shortening effect on the KCNQ1-V254M or KCNH2-G604S iPSC-CMs, all three SGLT2i compounds shortened the APD90 of the SCN5A-P1332L iPSC-CMs after 1 hour of treatment from 463±5 ms to 432±6 ms (EMPA, 18.8% attenuation, p=0.0002), 459±8 ms to 430±5 ms (CANA, 17.5%, p=0.004), and 453±6 ms to 434±4 ms (DAPA, 11.4%, p=0.01). Additionally, IC iPSC-CMs treated with 5 μM of ATXII induced significant APD prolongation from 318±9 ms to 379±12 ms (p=0.0003) after 30 min incubation. However, co-incubation of ATXII and SGLT2i abolished the APD prolonging effect of ATXII.

Conclusions:
Therapeutically inhibiting SGLT2 effectively shortens the cardiomyocyte APD in human heart cell models of the LQT3, but not LQT1 or LQT2. This pre-clinical data compels further assessment of SGLT2i as a novel therapy for patients with congenital LQT3.
Abstract 11574: Relationship Between Baseline Electrocardiographic Parameters and Outcomes in Patients With High-Risk Heart Failure With Reduced Ejection Fraction: Insights From the Vericiguat Global Study in Patients With Heart Failure With Reduced Ejection Fraction (VICTORIA) Trial
Authors: Yogasundaram Haran , Zheng Yinggan , Ly Eric , Ezekowitz Justin A , OConnor Christopher M , Blaustein Robert O , ROESSIG Lothar , Temple Tracy C , Westerhout Cynthia M , Armstrong Paul W , Sandhu Roopinder
Published: June 2023

Background:
Patients with chronic heart failure with reduced ejection fraction (HFrEF) and recent decompensation are at high risk of cardiovascular (CV) events including mortality; risk stratification remains challenging. To further assess risk in this population, we characterized their baseline 12-lead ECGs and their prognostic value in 4880 patients (24% female) from the VICTORIA study.

Methods:
Baseline ECG parameters were interpreted in a core laboratory blinded to centrally adjudicated clinical outcomes. There were 1799 primary composite events (time to first HF hospitalization (HFH) or CV death) and 1005 total all-cause deaths (21% sudden). The MAGGIC-adjusted association between baseline ECG parameters and outcomes are presented as hazard ratio (HR) and 95% confidence intervals (CIs).

Results:
Incidence rates of baseline ECG parameters and their association with all-cause death and the primary composite outcome are shown below. The median MAGGIC score was 24 (19, 28) points. Higher heart rate, greater QRS duration, and prolonged QTc were significantly associated with the primary composite and all-cause death (
Table
), as well as for CV death ([HR 1.04, 95% CI 1.02-1.07; p<0.001] [HR 1.02, 1.00-1.04; p=0.015] [HR 1.16, 1.00-1.34; p=0.049]), respectively. Sex-based interactions were evident for contiguous Q waves on all-cause death (male: HR 0.98, 0.82-1.17; female: HR 1.56, 1.15-2.12; interaction p=0.010) and CV death (male: HR 1.03, 0.85-1.25; female: HR 1.66, 1.17-2.34; interaction p=0.019). Additionally, contiguous Q-waves were associated with sudden death (HR 1.45, 1.05-2.00; p=0.022) and appeared to double the risk in females (male: HR 1.25, 0.87-1.79; female: HR 2.50, 1.23-5.06; interaction p= 0.087).

Conclusion:
Routine ECG parameters are associated with worse outcomes in high risk HFrEF patients—particularly in females with contiguous Q waves.
Abstract 11581: False Positive Troponin Elevation Due to Heterophile Antibody
Authors: Chien-Hale Morgan , Bernstein Hannah
Published: June 2023

Introduction:
While highly specific, false positive Troponin I (TnI) can be caused by heterophile antibodies, autoimmune phenomena, and fibrin interference. The overreliance on TnI levels can lead to unnecessary patient work-up. Here we present a case of chronically elevated troponin over several hospitalizations most consistent with viral heterophile antibody cross reactivity.

Case:
A 71-year-old man with diabetes and polio-related paraplegia was admitted for pharyngitis. Initial TnI assay was significantly elevated at >90 (normal < 0.04 ng/mL) with a CK-MB of 21.7 (normal <20.0 U/L). ECG showed no evidence of ischemia (Figure 1). He had similar TnI elevation on two prior hospitalizations, with no significant coronary artery disease on angiography. Despite the absence of chest pain and normal ECG and TTE, myocardial perfusion stress test was performed due to the elevation in CK-MB, which was negative for ischemia (Figure 2). Troponin T, a sendout lab, was <12 ng/L. Patient was later confirmed to have positive CMV IgG and positive EBV viral capsid and nuclear antigen IgG, supporting the mechanism of heterophile antibody cross reactivity as the mechanism for false positive troponin.

Discussion:
Our case demonstrates a growing literature of patients presenting with chronically elevated TnI unrelated to myocyte damage. Focus of troponin levels without consideration of overall clinical picture and previous medical history can lead to unnecessarily invasive and expensive testing. For this patient, elevated troponin led to unnecessary testing and prolonged hospital admissions despite consistently negative cardiac workup. Heterophile cross reactivity can lead to false positive TnI in 1:2000 patients. If elevated troponin is concerning for a false positive, evaluation through other markers should be considered before undergoing more invasive procedures.
Abstract 11584: Systemic Inflammation and Coronary Plaque Among Asymptomatic US Adults - Insights From the Miami Heart Study at Baptist Health South Florida
Authors: Lahan Shubham , Cainzos Achirica Miguel , Valero Elizondo Javier , Ali Shozab S , Arias Lara , Saxena Anshul , Feldman Theodore , Blaha Michael J , Shapiro Michael D , Blankstein Ron , Sharma Garima , Cury Ricardo C , Budoff Matthew , Fialkow Jonathan , Nasir Khurram
Published: June 2023

Objective:
We aimed to evaluate the association between inflammatory markers and coronary plaque as detected on coronary computed tomography angiography (CCTA) in an asymptomatic adult population.

Methods:
Data from Miami Heart Study — an ongoing prospective cohort study from the Greater Miami Area were used for this cross-sectional analysis. Exposures of interest were C-reactive protein (CRP; <2 vs ≥ 2mg/L) and Interleukin-6 (IL-6; in tertiles). The outcomes of interest were CCTA-based plaque findings: any plaque, CAC>0, CAC>100, maximal stenosis >50%, and high-risk plaque. Multivariable logistic regression models were constructed to evaluate the association between inflammatory markers and coronary plaque features.

Results:
We evaluated 2,359 patients (50.4% men), mean age 53.4±6.7 years. The largest racial/ethnic groups were Hispanics (47%) and non-Hispanic Whites (43.1%). Of the total cohort, 8.3% had diabetes, 56.2% were hypertensive, and 22.3% used statins. After adjusting for age, sex, race/ethnicity, CRP ≥2 mg/L was associated with increased odds of detection of any plaque on CCTA [odds ratio (OR), 1.31 (95% CI, 1.09-1.58)] and stenosis ≥ 50% [OR, 1.69 (95% CI, 1.18- 2.41)]. Likewise, IL-6 levels in 3
rd
tertile had higher odds of detecting any plaque and ≥50% stenosis by 1.6 and 2.5 folds, respectively (
Figure
); and were also associated with a CAC >100 [OR, 1.69 (95% CI, 1.09 - 2.61)]. Further adjustment for LDL-C, diabetes, and tobacco use attenuated these associations. In contrast, no significant associations were observed with having high-risk coronary plaque.

Conclusions:
Elevated levels of CRP and IL-6 are associated with presence of coronary plaque & stenosis on CCTA adjusted for demographics. However, these associations are markedly attenuated when adjusted for additional cardiovascular risk factors. Our findings suggest a role of systemic inflammation as a mediator of the effect of cardiovascular risk factors on coronary plaque burden.
Abstract 11586: Therapeutic Potential of Alpha Lipoic Acid in a Rat Model of Superimposed Preeclampsia: Effect on Maternal Signs, Placental Development and Fetal Growth
Authors: Barrientos Gabriela , Incardona Claudio A , Giardina Graciela , Uceda Ana M , Sgariglia Ma Alejandra , Galleano Monica , Garcia Silvia I
Published: June 2023

Introduction:
Superimposed preeclampsia (SPE) occurs in 25-40% of pregnant women affected by chronic hypertension and is associated with adverse maternal and neonatal outcomes. In previous studies, we have demonstrated that pregnant Stroke-prone Spontaneously Hypertensive Rat represent a spontaneous SPE model, characterized by defective trophoblast invasion and placental oxidative stress, asymmetric fetal growth restriction and worsening maternal hypertension with renal dysfunction towards term. Here, we sought to evaluate the therapeutic potential of alpha lipoic acid (ALA), a potent antioxidant, during early pregnancy in this model.

Methods:
Congenic timed breedings were established using SHRSP and Wistar Kyoto (WKY) females (10-12 weeks old, 200-250 g body weight, N = 10 animals/day analyzed). Upon vaginal plug detection (gestation day (GD)1), dams were assigned to two groups: ALA treatment, injected 25mg/kg body weight ALA i.p. on GD1, GD8 and GD12 and controls, receiving saline following the same protocol. Systolic blood pressure (SBP) profiles throughout pregnancy were recorded using a noninvasive volume pressure recording device. On GD20, animals were euthanized and fetoplacental specimens isolated for morphological and molecular analyzes. Statistical analysis was run on GraphPad Prism v 8.0, using 2 way ANOVA. Statistical significance was set at p˂ 0.05.

Results:
Treatment with ALA prevented the pregnancy-dependent SBP increase typical of the SHRSP model (SBP GD14 SHRSP: 169.3±2.1 mmHg vs. SHRSP+ALA: 146.1±3.4, p˂0.001). Furthermore, fetuses carried by ALA-treated SHRSP displayed increased weights (SHRSP: 1.75±0.05g vs. SHRSP+ALA: 1.99±0.01g, p˂0.05) and decreased cephalization indexes on GD20, indicating an improvement in the asymmetric growth restriction pattern. Treated dams also presented increased numbers of glycogen trophoblasts (PAS
+
cells) in the junctional zone and an enhanced vessel density on Isolectin B4
+
staining, suggesting an improved placental function.

Conclusions:
ALA administration during early pregnancy in the SHRSP model ameliorated maternal signs and improved placental function and fetal growth, emerging as a novel therapeutic intervention in pregnancies affected by chronic hypertension
Abstract 11587: Intriguing Genetic Overlap Between SCAD and TAD
Authors: Jeoffrey Syeda Manahil Haider Jeoffrey , Kalyanasundaram Asanish , Zafar Mohammad , Ziganshin Bulat A , Elefteriades John A
Published: June 2023

Importance:
Thoracic aortic dissections (TAD) are a well-known vascular cause of sudden death. Spontaneous coronary artery dissections (SCAD) are emerging as an important cause of early-onset myocardial infarction and sudden death. Genetic variants in multiple connective tissue genes have been recognized to underlie TAD; other genetic variants have similarly been recognized to underlie SCAD. Little data is available regarding any genetic commonality between TAD and SCAD.

Objective:
To determine any genetic overlap between genes coding for TAD and SCAD.

Methods:
Extensive review of 17 various retrospective and prospective clinical studies published between 2016 and 2022 exploring genetic studies of TAD and SCAD was performed using PubMed and Orbis. Articles highlighting the significant plausible triggers for TAD or SCAD were analyzed. Separate lists of causative genes were constructed for TAD and SCAD—and then commonalities sought. A Venn diagram was constructed to display the genetic overlap and common physiological pathways involved.

Results:
We identified a definite, meaningful overlap of fourteen independent genes based on GWAS or other genetic methods. Associated genetic pathways involved various biological processes including: Elastin degradation, smooth muscle cell function and the TGF-pathway. Overlapping genes included the following: COL3A1, TGFB2, SMAD3, MYLK, TGFBR2, TGFBR1, LOX, FBN1, NOTCH1, ELN, COL5A1, COL5A2, COL1A2, MYH11. Corresponding molecular pathways were investigated and correlated for both diseases.

Conclusions and relevance:
We are not aware of other studies searching for genetic commonalities between TAD and SCAD. We have successfully identified overlapping genes—and their corresponding molecular pathways—for TAD and SCAD. We hope these insights will lead to further clinical and scientific understanding of each disease via study of their fundamental commonalities.
Abstract 11592: Real-World Performance of Heartlogic Index in Subjects With CRT and ICD Devices
Authors: Wariar Ramesh , Boehmer John , Averina Viktoria A , Thakur Pramodsingh , Kwan Brian , Ruble Stephen B , Singh Jagmeet
Published: June 2023

Introduction:
The HeartLogic heart failure (HF) diagnostic was developed from data in subjects implanted with CRT-D devices. Diagnostic performance in subjects with ICDs (without CRT) is less well characterized.

Objective:
Compare HeartLogic performance in ICD and CRT subgroups.

Methods:
Data from US post-market HeartLogic CRT/ICD devices were directly linked with Medicare claims and subjects with continuous Medicare Part A&B fee-for-service coverage were analyzed. Claims HF events (HFE) were defined using primary HF diagnosis codes (DRG 291-3, I50.xx) and included acute inpatient events, and outpatient events with IV diuretic therapy. Baseline characteristics included patient demographics, implant data, and claims chronic conditions flags (CCFs). Diagnostic performance was defined as the sensitivity to detect HFEs and the false-positive alert rate (FPR), from which a modified receiver operator characteristic (ROC) curve was generated. Continuous variables were expressed as mean±SD and categorical variables as proportions. Two-sided 95% confidence intervals (CI) were calculated for sensitivity (binomial distribution) and FPR (negative binomial model).

Results:
Out of 4190 subjects,1567 linked subjects were included in the analysis with an average follow-up of 1.4±0.5 years. The CRT group (N=1078, 69%) was more likely to be Caucasian (88% vs 82%), less likely to have
de novo
devices (62% vs 80%), more likely to have CCFs of AF (43% vs 33%) and congestive HF (89% vs 75%), and a HF hospitalization in the year prior to implant (23% vs 16%). CRT and ICD groups provided 296 and 139 HFEs for performance evaluation. HeartLogic ROCs were similar in both groups with no difference in the nominal sensitivity (83% [CI: 78, 87] vs 80% [72, 86%],
p
=0.41) or FPR (1.386 [CI: 1.337,1.511] vs 1.322 [1.238,1.488],
p
=0.41).

Conclusions:
HeartLogic diagnostic performance determined using real-world claims data was not different in subjects implanted with ICDs and CRT-Ds.
Abstract 11598:
In Silico
Identification of Immunogenic Cardiac Troponin I Epitopes and Validation in Patients Treated With Immune Checkpoint Inhibitors
Authors: Xu Shirley , Pechenik Peninah , Kattel Sharma , Sonkawade Swati D , Nepali Sarmila , Ito Fumito , Sharma Umesh C , Pokharel Saraswati
Published: June 2023

Introduction:
Immune checkpoint inhibitors (ICIs) have contributed to the recent decline in death due to cancers like melanoma. However, serious cardiotoxic side effects (like fatal myocarditis) have been reported. Autoimmunity against cardiac proteins has been suspected but the underlying mechanism is not known.

Hypothesis:
ICI treatment induces the formation of autoantibodies against immunogenic sequences of cardiac troponin I (cTn I).

Methods:
We identified antigenic sequences in cardiac myosin and troponin I by bioinformatic analyses, including T- and B-cell epitope prediction methods. The sequences with the highest antigenicity scores were coated on plates for enzyme-linked immunosorbent assays (ELISAs). Sera from ICI-treated mouse models and patients were used as primary antibodies to detect self-reactivity against these peptides. Mice were treated every 3 days with a total of 17 doses of PD-1, CTLA-4, a combination of both, or isotype IgG control antibodies (Abs). For clinical samples, sera was taken from 26 ICI-treated patients with melanoma, including pre-treatment samples from 20 patients.

Results:
From the
in silico
analysis, we identified 5 cTn I and 2 myosin sequences as antigenic. Using ICI-treated mouse serum, we screened these peptides and found cross-reactivity with cTn I peptide T5, which reflects a flexible linker and portion of a helix in cTn I. After completing ICI treatment in mice, there was significant reactivity to T5 in combination treatment versus control (Absorbance: IgG 0.135±0.037, CTLA-4+PD-1 Abs 0.247±0.060, IgG vs. CTLA-4+PD-1 Abs p=0.02, n=5-9). There were also increased autoantibodies in combination treatment compared to CTLA-4 Abs (CTLA-4 Abs 0.123±0.040, CTLA-4 vs. CTLA-4+PD-1 Abs p=0.001, n=9-10). In our clinical studies, there was positive reactivity against peptide T5 of 6-7 fold change in 4 subjects (15% of patients) with late stage melanoma after the initiation of ICI therapy, as compared to the average pre-treatment value.

Conclusions:
Our study showed that ICI-therapy induced immune-reactive antibodies directed against antigenic targets of cTn I in both animal models and patients. These data suggest a novel mechanism of ICI-induced cardiotoxicity, which warrants further investigation.
Abstract 11601: Association Between Remnant Cholesterol and Coronary Plaque Features: The Miami Heart Study at Baptist Health South Florida
Authors: Quispe Renato , Mszar Reed , Lahan Shubham , Valero Elizondo Javier , Budoff Matthew , Cury Ricardo C , Feldman Theodore , Arias Lara , Blaha Michael J , Shapiro Michael D , Blankstein Ron , Sharma Garima , Cainzos Miguel , Nasir Khurram , Fialkow Jonathan
Published: June 2023

Introduction:
Remnant particles, the product of partial metabolism of triglyceride-rich lipoproteins, have been associated with atherosclerotic cardiovascular diseases (ASCVD), independent of low-density lipoprotein cholesterol (LDL-C). This study aims to further examine the role of remnant cholesterol (RC) in atherogenesis by assessing its association with plaque characteristics.

Methods:
After excluding individuals on statin therapy (n=527), we included 1,832 statin-naïve participants from the Miami Heart Study, a prospective cohort of clinical ASCVD-free individuals in Miami (2015-2018) evaluated using coronary computed tomography angiography (CTA). RC was estimated as non-high density lipoprotein cholesterol minus LDL-C. Multivariable logistic regression models were used to estimate the association between low/high RC/LDL-C groups (defined by < or ≥ medians) and plaque features.

Results:
Mean age of participants was 52.5±6.7 years, 54% women, 49.5% Hispanic. Median LDL-C and RC were 129.1 and 21.6 mg/dL, respectively. For each SD increase in RC levels, the odds of having non-calcified coronary plaque increased (OR 1.19 [95% CI 1.07-1.33]) and so did the segmental involvement score (OR 1.05 [95% CI 1.01-1.09]) independent of traditional risk factors including LDL-C. The prevalence of coronary plaque features per RC/LDL-C group are shown in Table. Among those with low LDL-C, having high RC conferred a significantly higher risk of non-calcified plaque (OR 1.61 [95% CI 1.11-2.32]) compared to having low RC, although associations were not statistically significant with other plaque features (Table).

Conclusions:
In asymptomatic individuals with low LDL-C, elevated RC was independently associated with non-calcified plaque.
Abstract 11608: Differences in Genetic Variants and Common Genetic Regulators between Arrhythmogenic Cardiomyopathy and Arrhythmogenic Dilated Cardiomyopathy Identified Using Systems Genetics Approaches
Authors: Orgil Buyan-Ochir , Xu Fuyi , Alberson Neely , Lu Lu , Towbin Jeffrey A , Purevjav Enkhsaikhan
Published: June 2023

Introduction:
Prominent arrhythmias are features of arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic dilated cardiomyopathy (aDCM). Despite clinicopathological differences, these diseases share common genetic causes.

Hypothesis:
This study aimed to identify variants in ACM and aDCM and map the candidate genetic regulators using a mouse genetic reference population (GRP).

Methods:
Whole exome sequencing was performed on 226 individuals with ACM and 102 patients with aDCM. Bioinformatics analysis was applied to identify the pathogenic or likely pathogenic variants followed by direct sequencing confirmation. Expression quantitative trait loci (eQTLs) mapping to heart transcriptomes of GRP of BXD recombinant inbred (RI) mice was conducted in GeneNetwork (http://www.genenetwork.org).

Results:
In the ACM cohort, a total of 82 variants (MAF<0.01) in 24 genes have been confirmed being positive in 42 probands. Depending on the frequency of the identified variants, the top 10 genes (excluding TTN) with the most pathogenic variants were PKP2, MYH6, FLNC, RYR2, MYH7B, PLEC, JPH2, SYNE1, NRAP and POSTN. In the aDCM cohort, 141 pathogenic variants have been identified and 91 patients harbored at least 1 deleterious variant. The top 10 genes were RYR2, FLNC, MYH7, DSP, SCN5A,MYPN, NEBL, CTNNA3, ACAP6 and SLC22A5. We analyzed the distribution of the first principal component (PC1) of mRNA expression levels of those 10 genes (eigentraits) from each cohort in the heart across BXD strains. Interval mapping for PC1 eigentraits for ACM identified a significant eQTL (P<0.05) in the mouse genome at 24-36 Mb of chromosome (Chr) 6. In aDCM, interval mapping for PC1 eigentraits identified 3 suggestive eQTLs at Chr 5 (44-53 Mb), Chr 6 (32-34 Mb) and Chr 15 (82-84 Mb). Further gene exploration of these eQTLs suggested that Mtpn, Lep, Cyb5r3, Tspo, Slit2, and Ppargc1a could be common regulators that interact with those top ACM and aDCM genes.

Conclusions:
This study identified diverse genes in ACM and aDCM cases. Our joint human and mouse analysis using a systems genetics approach identified genetic regulators that could affected expression of genes with pathogenic variants in ACM and aDCM patients.
Abstract 11626: A Hepato-Cardiac FGF21 Axis Activates a Cardiac FGF21 Autocrine Mechanism That Causes Hypertrophy With Pressure Overload
Authors: Mia Sobuj , Sidiropoulou Rafailia , Hoffman Matthew , Markopoulou Eftychia , Selzman Craig H , Drakos Stavros G , Chaudhuri Dipayan , Drosatos Konstantinos
Published: June 2023

FGF21 is expressed mainly in the liver and other organs, including skeletal muscle and heart. It exerts its actions by binding to its receptors (FGFR) and the co-receptor β-klotho. Despite evidence about protective action of FGF21 in different animal disease models, elevated plasma FGF21 levels have been reported in patients with heart failure. Thus, it remains unknown whether elevation in human heart failure is part of the disease’s pathophysiology or a protective response. Staining of heart sections from end-stage heart failure patients showed increased FGF21 that correlated with higher plasma FGF21 levels. To assess the relative contribution of cardiac and extracardiac FGF21 in heart failure, we generated 3 animal models with cardiomyocyte- (CM-FGF21-KO), hepatocyte- (Alb-FGF21-KO) or skeletal muscle-specific FGF21 (MLC-FGF21-KO) deletion and subjected them to transverse aortic constriction (TAC) for 3 days, 2, 4, and 8 weeks. Hepatic expression and plasma levels of FGF21 were increased 3 days post-TAC. Cardiac FGF21 expression was also increased after 2 weeks of TAC. Surprisingly, the pro-hypertrophic effect of TAC was abolished in both Alb-FGF21-KO and CM-FGF21-KO mice. Interestingly, cardiac FGF21 expression was not increased in CM-FGF21-KO mice despite the high plasma FGF21 levels. The MLC-FGF21-KO mice were not protected. Thus, cardiomyocyte FGF21 upregulation mediates cardiac hypertrophy in response to pressure overload. To investigate if cardiomyocyte FGF21 expression is controlled by FGF21 that is released from the liver, we treated human AC16 cells with recombinant FGF21, which increased endogenous FGF21 mRNA and protein, pointing to an autoregulatory FGF21-based induction of cardiac FGF21 expression. This auto-regulatory loop was potentiated by increased expression of cardiac FGFR1 in wild-type mice subjected to TAC that was attenuated in CM-FGF21-KO mice. Accordingly, we observed increased pro-hypertrophic cardiac signaling (pAMPK, pERK,Bnp, Tnfα) in wild-type mice with TAC, but not in CM-FGF21 KO mice. Conclusively, a hepato-cardiac FGF21-based signaling axis governs cardiomyocyte FGF21 expression, which accounts for cardiac hypertrophy. Inhibition of either hepatic or cardiomyocyte FGF21 is cardioprotective.
Abstract 11630: Wearable Cardiac Defibrillator Use is Associated With Lower All-Cause Mortality in Patients With Ischemic Cardiomyopathy: A Systematic Review and Meta-Analysis
Authors: Saeidifard Farzane , CHEN LU , Prokop Larry J , Budzikowski Adam S
Published: June 2023

Introduction:
Wearable cardiac defibrillators (WCD) have been shown to be effective for detection and treatment of ventricular tachyarrhythmias. However, their efficacy in improving survival or decreasing mortality in patients with newly diagnosed cardiomyopathy (CM) is uncertain. This study reviews the current available evidence.

Method:
We searched databases since inception to April 2022, without language and year of publication restriction for randomized trials and cohort studies that examined the difference between WCD use and non-use in mortality and survival among patients with ischemic and non-ischemic CM. Two independent investigators screened the abstracts and full texts and extracted the data. Data was analyzed using random effect model.

Results:
From 603 records identified by a librarian, only 4 randomized trials on WCD use in ischemic CM met the inclusion criteria. One of them was an abstract without any full text published. The total participants were 18,779 of which 2,408 were in the WCD group (mean age 65.12±11.5, 20.7% female) and the rest in control group (mean age 65.45±11.36, 28% female). The adjusted all-cause mortality at 3 months follow up was significantly lower in WCD group (RR 0.32, CI [0.11-0.97], including three studies, 2,360 patients in WCD group and 4,954 in control group) (heterogeneity score I
2
=86%)(figure). Adjusted all-cause mortality at 12 months was also significantly lower in WCD group (RR 0.43, CI [0.25-0.71], two studies, 857 patients in WCD group and 15,566 in control group) (heterogeneity score, I
2
=49%). Only one study reported adjusted risk for arrhythmic death, myocardial infarction, arrhythmia (atrial or ventricular), stroke and hospitalization. In addition, one study reported the difference in cost and healthcare use between the two groups.

Conclusion:
Our meta-analysis confirms significant reduction in all-cause mortality associated with WCD use in patients with newly diagnosed ischemic cardiomyopathy.
Abstract 11639: Effect of Diabetes Mellitus on Clinical Phenotype and Cardiovascular Mortality in Non-Ischaemic Dilated Cardiomyopathy
Authors: Hammersley Daniel J , Jones Richard E , Mach Lukas , Owen Ruth , Lota Amrit S , Khalique Zohya , de Marvao Antonio , Gulati Ankur , Baruah Resham , Guha Kaushik , Ware James S , Cleland John G , Pennell Dudley J , Halliday Brian P , Tayal Upasana , Prasad Sanjay K
Published: June 2023

Introduction:
Diabetes mellitus (DM) is common amongst patients with heart failure (HF) and associated with adverse outcomes. Historically this has been attributed to the association with atherosclerotic disease. We assessed the effect of DM on phenotype and outcomes in patients with non-ischaemic dilated cardiomyopathy (DCM).

Methods:
Prospective observational cohort study of 727 patients with DCM. All underwent a cardiac MRI and long-term follow up. The primary endpoint was CV death.

Results:
Of 727 patients with DCM (472 men, mean age 55 years, median LVEF 40%), 88 (12.1%) had DM at enrolment, of whom 19 (21.6%) were managed with insulin, 52 (59.0%) with oral hypoglycaemic agents (OHA) alone and 17 (19.3%) by diet alone. Enrolment predated guideline recommendations for SGLT2 inhibitors for HF. Patients with DM were older, had higher BMI, higher NYHA class, more were hypertensive and treated with loop diuretics (all p<0.001), ACEi/ARB (p=0.02) and mineralocorticoid receptor antagonists (p=0.002). Compared to patients without DM, those with DM had lower LVEF (mean difference -4% [95%CI -7 to -1], p=0.007) and more had myocardial fibrosis (OR 1.81 [1.13 to 2.91] adjusted for age and sex). After median follow up 7.7 years, 71 patients died from CV causes. DM was associated with higher cumulative incidence of CV death on univariate analysis (log rank p<0.001, Figure), but not after adjusting for age, sex, LVEF, NYHA, fibrosis, LAVi and RVEF (HR 1.66, 0.91 to 3.02, p=0.10). Patients with DM treated with insulin or OHA were at greater risk of CV death even after adjusting for the above variables (HR 2.02, 1.11 to 3.67, p=0.04). DM managed by diet alone was not associated with excess risk.

Conclusions:
DM is associated with adverse LV remodelling and fibrosis in patients with DCM; the subset requiring OHA or insulin had worse CV prognosis. Risk factor and lifestyle management may improve outcomes. Further studies are needed to assess whether added risk is attenuated by SGLT2 inhibitors.
Abstract 11652: What is the Relative Risk for Elevated Liver Function Tests of Single and Combined Statin and Alcohol Use and Implications for Management?
Authors: Horne Benjamin D , Le Viet T , May Heidi T , Knight Stacey , Bair Tami L , Muhlestein Joseph B , Knowlton Kirk U , Anderson Jeffrey L
Published: June 2023

Introduction:
Statins play a critical role in primary and secondary ASCVD prevention. Although uncommon, myalgias and abnormal liver function tests (LFTs) may limit statin use. Alcohol consumption also is a common cause of LFT elevations. It is unknown whether or to what extent concurrent alcohol and statin use may alter elevated LFT risk and impact management.

Methods:
Patients (pts) enrolled in the Intermountain INSPIRE registry who completed a health questionnaire for alcohol and other socioeconomic, dietary, and physical activity data were studied. Demographics, anthropometrics, cardiac risk factors, comorbidities, medication use, and laboratory results were obtained from electronic health records. Associations of alcohol and statin use with high ALT (females, >40 U/L; males, >55 U/L) were tested. Alcohol categories were: non-drinkers (ND; n=2797), moderate drinkers (MD; ≤7 drinks/week, n=980), and heavy drinkers (HD; >7 drinks/week, n=164).

Results:
High ALT was found in 18.9%, 12.6%, and 10.5% of HD, MD, and ND respectively (p=0.002) and in 11.3% of both statin (n=2154) and non-statin users (n=1787) (p=0.97). After adjustment, HD vs. ND had OR=2.19 (CI: 1.44, 3.33; p<0.001), and MD vs ND had OR=1.09 (CI: 0.86, 1.37; p=0.49). Pts not on statins had high ALT in 15.4% of HD (OR=1.47, CI: 0.73, 2.95; p=0.28) and 12.0% of MD (OR=1.10, CI: 0.79, 1.54; p=0.57) compared to 11.0% of ND. In parallel, pts on statins had high ALT in 21.2% of HD (OR=2.58, 95% CI: 1.52, 4.36; p<0.001) and 13.0% of MD (OR=1.16, CI: 0.85, 1.59; p=0.34) vs. 10.2% of ND. Despite these trends, no formal interaction was found between statin use with HD (p-interaction=0.27) or with MD (p-interaction=0.43). Results for high AST (>40 U/L) and low ALP (<40 U/L) were similar to the ALT findings.

Conclusions:
In this prospective database, statin use was not associated with abnormal LFT findings, whereas risk was higher with increasing alcohol consumption. Concurrent statin and alcohol use was associated with a modestly elevated risk of abnormal LFT, but the interaction was not significant. Reducing alcohol consumption rather than reducing or discontinuing statins may reverse abnormal LFT while preserving the preventive benefit of statins. This hypothesis deserves further prospective testing.
Abstract 11680: Modified versus Standard Endomyocardial Biopsy Technique: A Comparison of Fluoroscopy Time, Total Procedure Time, and Complications
Authors: Rizzi Scott , Krauspe Ethan , Zhang Chong , Lui Charles
Published: June 2023

Background:
Patients who have undergone orthotopic heart transplant (OHT) undergo frequent endomyocardial biopsies (EMBx) to assess for rejection. Difficulty crossing the superior venous caval anastomosis and tricuspid valve often complicates these procedures. We studied a new approach in which a peel-away sheath is placed in the right internal jugular vein through which a Swan-Ganz catheter is then inserted and advanced. Following right heart catheterization, the peel-away sheath is removed and a long biopsy sheath is advanced over the Swan-Ganz catheter, which is then removed, leaving the long sheath behind for advancement of the bioptome into the right ventricle.

Objective:
To compare fluoroscopy (fluoro) time, procedure time, and complications between a modified and standard approach to EMBx.

Methods:
We included patients who underwent OHT and had EMBx data available for review at two University-affiliated institutions. We excluded EMBx cases that combined a left heart catheterization. We compared fluoro time and procedure time between modalities using mixed effects gamma regression with operators and patients both included as random effects.

Results:
We analyzed 964 (198 modified, 766 standard) EMBx cases in 71 patients who underwent OHT from 2017 to 2022. The mean patient age was 53.9 at time of OHT; 14% (n=10) were female. Median fluoro time was 2.8 and 4.9 minutes, and median procedure time was 27 and 29 minutes, for the modified and standard approach, respectively. Cases performed using the modified approach had a shorter fluoro time by 28%, and a shorter procedure time by 7% as compared to the standard approach (Ratio=0.72, 95% CI: 0.62 ~ 0.84, p<0.001 for fluoro time; Ratio=0.93, 95% CI: 0.87 ~ 0.98, p=0.014 for total procedure time). Only one complication was identified.

Conclusion:
In this cohort, a modified approach to EMBx was associated with reduced fluoroscopy and procedure time as compared to the standard approach with no difference in complications.