bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 14241: Cigarette Smoke Causes Atrial Fibrillation via PiP2 Signaling
Authors: Chidipi Bojjibabu , Chang Mengmeng , Abu-Assail Obada , Reiser Michelle , Tian Zhi , Allen-Gipson Diane , Noujaim Sami F
Published: April 2024

Introduction:
Cigarette smoking (CS) is a major cause of cardiovascular diseases. Smokers are at a significantly higher risk for developing atrial fibrillation (AF), a dangerous and abnormal heart rhythm. In the US, 15.5% of adults are current smokers, and it is becoming clear that CS is an independent risk factor for AF, but a detailed mechanistic understanding of how CS contributes to the molecular patho-electrophysiology of AF remains elusive. We investigated if CS related AF is in part mediated through a mechanism that depends on the cardiac acetylcholine activated inward rectifier potassium current (I
KACh
).

Hypothesis:
We tested the hypothesis that CS stimulates phosphatidylinositol 4-phosphate 5-kinase alpha (PIP5K) signaling, leading to increased cellular phosphatidylinositol 4,5- bisphosphate (PiP2) levels, and subsequent I
KACh
activation and AF perpetuation.

Methods:
We used patch clamp in HEK293 cells expressing Kir3.1 and Kir3.4, the molecular correlates of IKACh, cultured in the presence of 5% CS extracts. In vivo inducibility of AF was assessed in mice exposed to CS for 8 weeks.

Results:
In HEK293 cells, 24 h incubation with CSE increased the cellular PiP2 levels, and increased I
KACh
. Addition of 5 uM ISA, an inhibitor of PIP5K, abrogated the CS effects on I
KACh,
indicating that CS activates PIP5K. Finally, intrajugular injection of tertiapinQ, an I
KACh
blocker, terminated atrial fibrillation in mice exposed to CS for 8 weeks.

Conclusions:
Cigarette smoke modifies the atrial electrophysiological substrate, leading to arrhythmogenesis, in part, through I
KACh
activation by increasing the cellular levels of PiP2.
Abstract 14267: Comprehensive STEMI Protocol Enhances Process and Care Metrics in Patients With In-Hospital STEMI
Authors: Kassis Nicholas , Nair Raunak , Kumar Anirudh , Huded Chetan , Johnson Michael , Kravitz Kathleen A , Reed Grant W , Krishnaswamy Amar , Menon Venu , Lincoff A M , Kapadia Samir R , Khot Umesh N
Published: April 2024

Introduction:
Patients who experience in-hospital ST-elevation myocardial infarction (iSTEMI) represent a uniquely high-risk cohort owing to delays in diagnosis and time to reperfusion as well as substantially increased mortality. Quality initiatives aimed at improving the care of this vulnerable, yet understudied population are needed.

Methods:
This study included consecutive patients with iSTEMI treated with percutaneous coronary intervention (PCI) between 01/01/2011-07/15/2019 at a single, tertiary referral center. A comprehensive iSTEMI protocol (CSP) was implemented on 7/15/2014, incorporating: (1) nursing chest pain protocol, (2) improved electronic access to ECG images, (3) checklist for initial triage and management, (4) 24/7/365 catheterization lab readiness, and (5) radial-first PCI approach. Key metrics and outcomes were compared before and after CSP implementation.

Results:
Among 132 total subjects, the post-CSP cohort (n=84) were older with more males and active smoking relative to the pre-CSP cohort (n=48). After CSP adoption, we observed significant reductions in median door-to balloon time (D2BT) from 107 minutes to 64 minutes (p<0.001), median fluoroscopy dose from 1.6 Gy to 1.2 Gy (p=0.04), and mean contrast load from 181mL to 148mL (p=0.02), with simultaneous increases in goal D2BT from 39% to 74% of patients (p<0.001) as well as radial use from 15% to 70% (p<0.001). Despite a numerical decrease in in-hospital mortality after CSP application from 17% to 10% (p=0.35), no significant differences were found in all outcomes including 30-day and 1-year mortality between groups.

Conclusion:
The implementation of a CSP was associated with marked improvements in critical process and care metrics among vulnerable patients who experience STEMI while hospitalized. Interestingly, these benefits failed to improve short or long-term outcomes including mortality, highlighting the underlying high-risk nature of this population.
Abstract 14280: Trends and Association of Payer Status With Outcomes in Injection Drug Use Related Infective Endocarditis, From National Inpatient Sample (2002-2017)
Authors: Khan Muhammmad Zia , Khan Muhammad U , Zahid Salman , Ullah Waqas , balla Sudarshan
Published: April 2024

Introduction:
Infective endocarditis (IE) associated with intravenous drug abuse (IDU) is rising in incidence in the United States. Few studies exist on the association of IDU in IE with primary payer and socio-economic status.

Hypothesis:
Type of primary insurance payer and socio-economic status in patients with IDU related IE may strongly correlate with inpatient morbidity and mortality.

Methods:
We used the United States National Inpatient Sample (NIS) data from the year 2002 to 2017. International Classification of Diseases (ICD)-9 and ICD-10 codes were used to identify all hospitalizations with IDU-IE above the age of 17 years. Pearson chi-square test and Mann Whitney U test were used for statistical testing. Multivariate logistic regression analysis was done for adjusted cohort.

Results:
Primary payers of 78,211 weighted admissions of patients with IDU-IE were identified. Most of the patients were Medicare/Medicaid (67.6%), followed by private insurance(13%) and self-pay(19.3%). Patients under Medicaid/Medicare were older (37yrs. [interquartile range (IQR), 29-47) as compared to private pay (34yrs. [IQR, 25-47]) and self-pay(34 yrs. [IQR,28-43]). Comorbid conditions like liver disease, viral hepatitis, peripheral vascular disease (PVD), renal disease, psychosis, depression, and AIDs were more common in Medicare/Medicaid population (Figure). Patients under private insurance had a higher median income. Patients under Medicare/Medicaid had higher adjusted mortality (1.162, [confidence interval (CI), 1.082-1.248]) as compared to private insurance (0.852, [CI, 0.764-0.95]) but no difference in adjusted mortality as compared to self-pay (OR, 0.927, [CI, 0.855-1.006]).

Conclusions:
The medical coverage of patients with IDU-IE over the years has increased, however, mortality is still higher in patients with Medicare/Medicaid as compared to private insurance, the reason behind this needs further exploration.
Abstract 14315: Invasive versus Conservative Strategy for Stable Coronary Artery Disease in Patients With Asymptomatic Heart Failure With Reduced Ejection Fraction
Authors: Al-seykal Ibragim , Dai Qiying , Bose Abhishek , Sharma Nitish , Shah Neeta , Ramsaran Eddison
Published: April 2024

Introduction:
In asymptomatic heart failure patients with reduced ejection fraction (HFrEF), an ischemia evaluation is part of the routine diagnostic work up. Nonetheless, in asymptomatic HFrEF patients with stable ischemic heart disease (SIHD) and intermediate to high-risk findings on nuclear perfusion study, the decision to pursue conservative medical therapy versus an early invasive strategy remains debatable. To address this conundrum, we performed a retrospective analysis.

Method:
A total of 451 patients with SIHD and HFrEF were followed for at least 16 months. All patients were classified as intermediate to high-risk based on their nuclear stress test results. Patients were subsequently dichotomized into two groups depending on whether they underwent an initial invasive approach versus continuing conservative medical therapy. A multivariable Cox regression analysis was performed to compare the primary outcome of all-cause mortality between the two groups.

Results:
Patients undergoing an initial invasive strategy were younger (68.3 ± 11.5 vs 71.3 ± 11.8 years, P = 0.001) and more likely to have a prior percutaneous coronary intervention (PCI, 50% ± 25.9% vs. 35% ± 13.6%, P = 0.001) compared to the medical therapy group. On multivariable analysis, after adjusting for demographics and confounding factors, there was no difference in all-cause mortality between the two groups (p= 0.120,
Figure
). An older age with a prior history of a PCI or a cerebrovascular accident (CVA) were independent predictors of mortality while a history of never smoking was associated with a mortality benefit.

Conclusions:
In asymptomatic HFrEF patients with SIHD with intermediate to high-risk findings on nuclear stress testing, an initial invasive strategy has no significant mortality benefit when compared to medical therapy. An older age, history of prior PCI or CVA predicted mortality while never smoking provided a mortality benefit.
Abstract 14323: Differential Complement Activation Following On- and Off-Pump Coronary Artery Bypass Surgery Explained by Alternative Pathway Activation
Authors: Buerke Michael , Boettger Priyanka
Published: April 2024

Introduction:
Coronary Artery Bypass Surgery (CABG) with the off pump (OFFCAB) technique may cause less inflammatory activation than using cardiopulmonary bypass (ONCAB). ONCAB procedures activate complement more but the relative contribution of classical and alternative pathways is unknown. We hypothesised OFFCAB procedures would produce less alternative pathway activation and performed a prospective, observational study to examine classical, alternative and final pathway activation in OFFCAB and ONCAB patients.

Methods:
Forty-two consecutive CABG patients were recruited over an 8 month period. At the discretion of the surgeon and patient, 26 underwent ONCAB and 16 OFFCAB procedures. Blood was taken pre, intra and post operatively for 24 hrs for assessment of inflammatory and ischaemic serum markers. Complement components Bb, C4d, iC3b and sC
5b-9
(i.e. the terminal complement complex or TCC) were assayed as markers of complement activation.

Results:
Most striking was a greater activation of the alternative pathway in the ONCAB group. Bb levels rose significantly (between pre- and 8hr post-operative time-points) following ONCAB based surgery (2.6 Vs 5.6 μg/ml respectively). OFFCAB surgery produced no significant alternative pathway activation. At peak alternative pathway activation (8hr post surgery), serum Bb levels were 1.7 fold higher in ONCAB vs OFFCAB patients (5.6 Vs 3.9 μg/ml respectively). These novel data reveal marked alternative pathway activation associated with ONCAB.Serum C4d analysis revealed that both procedures were both associated with a similar degree of classical pathway activation. In keeping with previous data, the TCC assay indicated significantly greater global complement activation by ONCAB than OFFCAB. Other inflammatory and ischaemic serum markers rose significantly and similarly in both groups.

Conclusion:
We provide the first analysis of on- and off-pump CABG in the activation of the classical, alternative and final complement pathways. ONCAB causes greater global complement activation. We conclude this may be largely due to activation of the alternative pathway by ONCAB, since OFFCAB did not significantly activate this pathway. Classical pathway activation was similar in both groups.
Abstract 14344: The Competing Roles of Glucose and Lipoprotein Lipase on Regulatory Macrophage Function
Authors: Bhatnagar Ashita , Alenghat Francis J
Published: April 2024

Background:
Atherosclerosis causes more death than any other pathophysiologic process. It has a well-established inflammatory, macrophage(MФ)-mediated component which can be stoked by uncontrolled diabetes. However, there are also protective, regulatory MФ processes that can help quell atherosclerosis. Lipoprotein Lipase (LPL) on the MФ surface can hydrolyze circulating triglyceride-rich lipoproteins into glycerol and free fatty acids to provide a non-glucose energy source. We hypothesized that regulatory MФs have high LPL activity, which would promote fatty acid metabolism to drive inflammation-resolving functions, and that this LPL activity is inversely related to ambient glucose.

Results:
MФs were cultured and differentiated from bone marrow harvested from wild-type mice aged 9-16 weeks. Two weeks after harvest, these MФs were polarized with (1) interferon-γ and lipopolysaccharide to stimulate classically-activated, inflammatory MФs or (2) interleukin-4 to stimulate alternatively-activated, regulatory MФs. The resulting phenotypes were validated by canonical transcript markers (
Tnfa
/
Nos2
for inflammatory MФs and
Ym1
/
Arg1
for regulatory MФs) and cell surface markers (CD86 and CD206, respectively). Using a triglyceride analog that fluoresces when cleaved by LPL, we found that regulatory MФs have far greater LPL activity than inflammatory macrophages at baseline (33 ± 2 vs 1 ± 0.2 a.u., p < 0.001, n=8). By varying glucose concentration during the polarization, this effect was most pronounced at normal, physiological concentrations of glucose (5 mM, ~90 mg/dL) and blunted at a high-glucose concentration that can be found in uncontrolled diabetes (25 mM). Each experiment was repeated across multiple batches of MФs (n≥4) and from multiple mice (n=15), male and female.

Conclusions:
Taken together, our findings support a model in which regulatory MФs are programmed to utilize LPL to drive the inflammation-resolving phenotype and that this process works best at low, physiologic glucose concentrations. Future translational work will investigate whether a lack of LPL-mediated regulatory MФ function is a reason why patients with uncontrolled diabetes have higher atherosclerotic burden and plaque instability.
Abstract 14349: Transcatheter Edge-to-Edge Mitral Repair versus Surgery in Medicare Patients
Authors: Chikwe Joanna , Roach Amy , Egorova Natalia
Published: April 2024

Background:
The optimal therapy for patients with primary mitral regurgitation eligible for transcatheter mitral edge-to-edge repair (TEER) and surgery is not known. This study compared mid-term outcomes of TEER and mitral surgery for primary mitral regurgitation.

Methods:
Centers for Medicare and Medicaid data was used to identify 158,931 adults who underwent mitral repair (42.9%, n=68,166) or TEER (14.5%, n=23,008) between July 2012 and June 2019. Patients undergoing mitral replacement (42.6%, n=67,757), previous mitral intervention (3.1%, n=4877), secondary, rheumatic or infectious etiology (26.3%, n=41,821), coronary or valve surgery (22.2%, n=35,438), and urgent procedures (15.6%, n=24,768) were excluded, and 4550 propensity matched patient pairs created. The primary outcome was 3-year survival. Stroke and mitral re-intervention were compared using competing risk analysis, with a landmark analysis of new atrial fibrillation (AF) after 30-days.

Results:
In the overall cohort patients undergoing TEER were older, with worse comorbidity and frailty than patients undergoing surgery. In propensity matched patients mean age was 77.3 vs. 76.4 years (P=NS) and frailty score was 0.2 vs. 0.19 (P=NS). Three-year mortality after surgery was 14% (standard error (SE) 0.02) versus 34% (standard error (SE) 0.03) after TEER (p<0.0001) (Figure). In competing risk analysis at three years stroke rates were similar (hazard ratio (HR) 1.07, 95% confidence interval (CI) 0.80-1.45), mitral reintervention was less common (HR 0.26, 95% CI 0.20-0.34); new AF was significantly less common (HR 0.82, 95% CI 0.7-0.96) after surgical repair compared to TEER.

Conclusion:
In propensity matched patients with primary mitral regurgitation surgical mitral repair was associated with superior survival, freedom from new AF and mitral re-intervention. This treatment difference, which may be due to selection bias, should be evaluated in randomized trials.
Abstract 14354: Optimal Anticoagulation Use in Patients Undergoing Transcatheter Mitral Valve Replacement a Quest for More Data
Authors: Vashistha Kirtivardhan , Tobaa Amel , Elhamdani Adee , Khalif Adnan , Doyle Mark , khalil ramzi
Published: April 2024

Background:
Multiple studies have demonstrated an increased risk of valve thrombosis in patients with mitral valve prostheses. Data to guide decision-making in regards to the choice of anticoagulation agent and duration of the therapy is lacking. We present our single-center experience with oral anticoagulation use in patients undergoing transcatheter mitral valve replacement (TMVR).

Methods:
32 patients underwent the TMVR procedure at our center from 1/1/2017 to 12/31/2020. Data points on baseline characteristics, STS-PROM, functional status (NYHA and KCCQ), baseline laboratory values, echocardiographic parameters (including LVEF, MV area, gradient, grading of MS, and MR was collected. We analyzed patterns of anticoagulation therapy including the type of agent, duration of therapy, and complications occurring related to anticoagulation use.

Results:
Our registry included 32 patients that underwent TMVR. 70.5 % were females, 96.8 % Caucasian with a mean NYHA class of 3.25. STS-PROM of 6.25 (5.56-9.43) and KCCQ score of 38.04 (SD 19.9). Out of 32 patients, 31 had retrievable data. Vitamin K antagonist (VKA) was used in 60 % (18), apixaban in 26.6 % (8), rivaroxaban in 16.6 % (3), and no anticoagulation was used in 0.03 % (1) of patients.74 % (22) of the patients were on anticoagulation at the time of TMVR for another indication. 33.3% (6) of patients on VKA suffered a complication such as gastrointestinal/genitourinary bleed, while 54.45% (6) of patients on DOAC reported similar complications.

Conclusion:
The choice of anticoagulant and optimal duration of anticoagulation in patients undergoing TMVR remains a gap in our evidence base. We present our single-center experience of anticoagulant use in this patient population. Further randomized studies are needed to address this knowledge gap.
Abstract 14379: Polypill Therapy and Risk of Adverse Cardiovascular Events and Mortality: A Systematic Review and Meta-Analysis
Authors: Rao Shreya , Siddiqi Tariq Jamal , Khan Mohammad S , Michos Erin , Navar Ann M , Wang Thomas J , Greene Stephen J , Prabhakaran Dorairaj , Khera Amit , Pandey Ambarish
Published: April 2024

Introduction:
Prior studies have reported improvements in population-level risk factor burden and cardiovascular outcomes using polypill strategy. We aimed to provide an updated meta-analysis of RCTs evaluating the efficacy of polypill-based strategy in reducing the risk of adverse cardiovascular outcomes.

Methods:
RCTs examining the association between polypill therapy and cardiovascular outcomes published before 2/1/2021 were included. The outcomes of interest were major adverse cardiovascular events (MACE) and all-cause mortality. Risk ratios for dichotomous outcomes were converted to log RR and pooled using a generic inverse variance weighted random-effects model. Data for continuous outcomes were pooled using random-effects modeling and presented as mean differences with 95% CIs.

Results:
Eight studies representing 25,584 patients were included for analysis. In pooled analysis, the use of polypills was associated with a non-significant reduction in the risk of MACE [RR(95% CI): 0.85(0.70-1.02)] and significant reductions in the risk of all-cause mortality [RR(95% CI): 0.90(0.81-1.00)]. The reductions in the risk of MACE with polypill use varied by baseline risk and nature of the study population [primary prevention (polypill, 476/10503; control, 684/10509) vs. secondary prevention (polypill, 170/2307; control, 153/2265)], with the most significant risk reduction among lower-risk cohorts, including within primary prevention populations [RR 0.70 (0.62, 0.79)]. Among CV risk factors, modest but significant reductions were observed for systolic and diastolic blood pressure, but not for levels of total or LDL-cholesterol. Polypill strategy was also associated with significantly improved drug adherence [RR(95% CI): 1.31(1.11-1.55)].

Conclusions:
. Polypill strategy is associated with significant reductions in cardiovascular risk factors and the risk of all-cause mortality and MACE, particularly in the primary prevention population.
Abstract 14385: Genome Sequencing and Re-Engineered Heart Cell-Disease Modeling Identifies a Novel Deep Intronic Variant in a Multi-Generational Long QT Syndrome Pedigree
Authors: Tobert Kathryn E , Tester David J , Zhou Wei , Haglund-Turnquist Carla , Giudicessi John , Ackerman Michael J
Published: April 2024

Introduction:
Most of long QT syndrome (LQTS) is explained by pathogenic variants in
KCNQ1
,
KCNH2
, or
SCN5A
. However, ~10-20% of LQTS index cases remain genetically elusive following commercial genetic testing. Here, we identified and functionally characterized a novel LQTS genetic substrate in a multi-generational, “genotype negative” LQTS pedigree.

Methods:
The index case was a 40-year-old female with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Although anticipated to have
KCNH2-
mediated LQT2, commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing and variant analysis was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 “gene-corrected” isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. RT-PCR was used to determine the effects of the identified variant on splicing. Action potential duration (APD) and field potential duration (FPD) were measured using voltage-sensing dye (Fluovolt) and microelectrode array, respectively.

Results:
No ultra-rare, nonsynonymous heterozygous variants co-segregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic
KCNH2
variant (c.3331-316 G>T) was present in all affected individuals. RT-PCR analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316 G>T creates a novel 89 base-pair exon residing between canonical exons 14 and 15 of
KCNH2
that results in a frame-shift variant annotated as p.S1112Pfs*171. The APD
90
was significantly longer in p.S1112Pfs*171-iPSC-CMs (647 ± 12 ms, n=50) compared to isogenic control iPSC-CMs (412 ± 10 ms, n=50, p < 0.0001). Further, the FPD was significantly longer in p.S1112Pfs*171-iPSC-CMs (349 ± 8 ms, n=48) compared to isogenic control iPSC-CMs (209 ± 10 ms, n=20, p < 0.0001).

Conclusions:
A novel deep intronic
KCNH2
variant was identified in a multi-generational genetically elusive LQTS pedigree. The patient-derived and isogenic control iPSC-CMs establish that the p.S1112Pfs*171-KCNH2 variant is the monogenetic cause for this family’s LQTS. As suggested by the phenotype, this family indeed has
KCNH2
-mediated LQT2 albeit stemming from a deep intronic variant
.
Abstract 14414: Embryonic Stem Cell Derived Exosomes Enhance Anti-Tumor Efficacy of Doxorubicin and Improve Cardiac Function in Triple-Negative Breast Cancer Xenograft Mice
Authors: Samidurai Arun , Das Anindita , Kraskauskas Donatas , Zhang Bei , Olex Amy L L , Liu Jinze , Hu Bin , Koblinski Jennifer , Singla Dinender K , Kukreja Rakesh C
Published: April 2024

Background:
Doxorubicin (Dox) is a potent chemotherapeutic drug widely used for the treatment of triple negative breast cancer (TNBC). However, Dox treatment results in inadvertent cardiotoxic effects which often require supplemental therapy. We previously showed that treatment with embryonic stem cells derived exosomes (ES-Exos) enhanced chemosensitivity of Dox in breast cancer cells. Here we tested the hypothesis whether adjuvant therapy with ES-Exos in mice with orthotopic TNBC xenograft can enhance the anti-tumor effect of Dox and improve cardiac function.

Methods and Results:
Athymic female nude mice (6-wk old) were injected with human MDA-MB-231-Luc cell line in mammary intraductal T4 region to generate orthotopic xenografts of TNBC. After 2 weeks of tumor growth, mice (n=10/group) were treated for 4 weeks with: Saline (Con); Dox (5 mg/kg/week); ES-Exos (50 μg, twice a week); Dox+ES-Exos; and MEF (50 μg/twice a week; non-stem cell exosomes derived from mouse fibroblasts). ES-Exos were labelled with ExoGlow-Vivo near-IR dye to track the localization of exosomes in the tumor. Treatment with Dox+ES-Exos and Es-Exos showed improved survival as compared to Dox (2 deaths) and Con (3 deaths)
(Fig.A)
. Tumor size was significantly reduced with Dox+ES-Exos and ES-Exos treatments as compared to Con and Dox treatment
(Fig.B)
. Cardiac function measured by echocardiography showed improved ejection fraction in Dox+ES-Exos and ES-Exos as compared to Con group
(Fig.C)
. Cell proliferation rate assessed by Ki-67 score with immunofluorescence showed significantly higher rate in Con as compared to Dox and Dox+ES-Exos groups. RNA seq analysis identified upregulation of unique antitumorigenic regulators such as Semaphorin 5 (Sema5) and FOXO15 in ES-Exos compared to MEF, which may contribute to the therapeutic effect.

Conclusion:
Treatment with ES-Exos may be a promising novel strategy to improve chemosensitivity with attenuation of its cardiotoxic effect in TNBC.
Abstract 14420: STIM and Orai Spatial Distribution in the Infarcted Mouse Heart Reveals Their Role in Fibroblast Activation
Authors: Gammons Jesse , Halpage Janith , Mancarella Salvatore
Published: April 2024

Introduction:
Heart failure (HF) remains a major source of late morbidity and mortality after myocardial infarction (MI). Calcium handling and the signaling pathways that govern the functional remodeling associated with HF are unclear. Store-operated calcium entry (SOCE) is a key factor in modulating Ca2+ signals. SOCE is mediated by the STIM protein and Orai channels. Monitoring STIM and Orai distribution is of great interest for studying cardiac remodeling after MI. This study investigated the spatial distribution of STIM and Orai in the heart after MI injury.

Methods:
The myocardial injury was induced in adult mice via ligation of the left anterior descending artery. MI- and sham-operated animals were euthanized, and hearts were harvested for ex-vivo analyses at 3, 7, 14, and 28 days after MI. We used western blot coupled with immunostaining to detect temporal and spatial profiling of specific STIM and Orai isoforms in different physiological zones and timepoints of MI to generate an integrative high-resolution map of STIM-Orai expression during cardiac remodeling.

Results:
We found that STIM1 and Orai1 proteins were upregulated from 3-day post-MI throughout day 28 post-MI, (3-4 fold times higher than controls, p<0.001). STIM1 and Orai1 were the most abundant isoforms present in the injured heart. In contrast, Orai3 expression was found to transiently increase at 3- and 7-day post-MI (1.5 fold, p>0.01), STIM2 and Orai2 expression did not change. Spatial pattern analysis revealed a marked gradient of STIM1 and Orai1 expression (decreasing from the border zone, the infarcted area, and the distal area). Co-labeling with cell-specific markers revealed that cardiac fibroblasts exhibited a high level of STIM1 and Orai1 expression. In vitro activation of cardiac fibroblasts showed a marked increase of STIM1 and Orai1 protein expression.

Conclusions:
Taken together, these data demonstrate that STIM1 and Orai1 expression is associated with fibroblast activation during fibrotic remodeling in the MI. Ca2+ signaling pathways that drive the expansion of fibrosis may rely on sustained STIM1 and Orai1 expression in scar formation and fibroblast activation, of which could provide future targets to exploit for treatment to prevent HF.
Abstract 14439: Complications With Medtronic’s SelectSecure 3830 Leads When Used for Atrial and Ventricular Pacing versus Conduction System Pacing in the United States
Authors: Jaisingh Keerthish C , Jiwani Sania , Thotamgari Sahith Reddy , Ponna Pramod Kumar , Dominic Paari
Published: April 2024

Introduction:
Conduction system pacing is physiological and is therefore gaining interest. The Medtronic SelectSecure 3830 lead was officially approved by the FDA for His-bundle pacing (HBP) in 2018. However, prior to 2017-2018, this lead was mainly used for atrial pacing, ventricular pacing, or both. We evaluated and compared nationwide adverse events and complications associated with this lead prior to and after 2017.

Hypothesis:
Compare adverse events and complications associated with Medtronic’s SelectSecure 3830 leads before 2017 when it was mainly used for atrial, ventricular, or atrial and ventricular pacing to events after 2017 when it was mainly used for HBP.

Methods:
We collected adverse event reports from the FDA’s Manufacturer and User Facility Device Experience (MAUDE) on SelectSecure 3830 leads between 2008 and 2020. We searched the data base with key words “selectsecure” and “select secure” along with the model number “3830” to aggregate the data. Duplicate entries were screened and removed, and the location the leads were used was classified.

Results:
Total number of adverse events reported before 2017 was 393 (90.5%) when compared to after 2017, 41 (9.5%). The percentage of adverse events reported when the lead was used for atrial, ventricular, or atrial and ventricular pacing was 95.3%, when compared to 4.7% when the lead was used for HBP. The most common adverse events reported were capture and threshold issues (16.8%; PRR for atrial/ventricular lead location 0.76 [95% CI: 0.32-1.78] vs. 1.30 [95% CI: 0.55-3.06] for His-bundle lead location) and lead dislodgement (15.6%; PRR for atrial/ventricular lead location 1.03 [95% CI: 0.27-3.81] vs. 0.96 [95% CI: 0.26-3.58] for His-bundle lead location); which were comparable.

Conclusion:
Medtronic’s SelectSecure 3830 leads had comparable capture/threshold and lead dislodgement issues regardless of the atrial, ventricular, or His-bundle location.
Abstract 14444: A Novel Role for the Hypothalamic Paraventricular Nucleus in Resuscitation From Opioid-Induced Respiratory Depression by Fentanyl in the Rat
Authors: Brackley Allison D , Truong Tamara , Contreras Jorge , Andrade Mary Ann , Toney Glenn M
Published: April 2024

Introduction:
Opioid receptor antagonists, like naloxone, reverses opioid-induced respiratory depression (OIRD). We recently found that systemic oxytocin reverses fentanyl OIRD in rats. Naloxone triggers a surge in oxytocin release from the hypothalamic paraventricular nucleus (PVN) in anesthetized rats.

Hypothesis:
Given that naloxone induces PVN oxytocin release, we hypothesized that the PVN, an unrecognized brain region for opioid overdose reversal, is capable of respiratory resuscitation following fentanyl OIRD.

Methods:
Naloxone (5 mg/kg, i.v.) was given to conscious rats with indwelling venous cannulae. Blood samples were extracted at 5 min post-naloxone to measure plasma oxytocin by ELISA. Under anesthesia, phrenic nerve activity was recorded in vagotomized, paralyzed, and artificially ventilated rats to quantify inspiratory drive following fentanyl (60 nmol/kg, i.v.) and assess OIRD reversal potential following unilateral PVN nanoinjection of naloxone (3 nmol/kg, 50 nL) or vehicle (50 nL). In spontaneously breathing mice with channelrhodopsin expressed exclusively in oxytocin neurons, expired CO
2
was used to monitor rhythmic ventilation and to quantify bradypnea during OIRD. Following fentanyl, blue light (473 nm, 12 mW) pulses (10 ms, 20 Hz) or dummy pulses were delivered to the PVN using a 5 s On/1 s Off pattern for 3 min.

Results:
Systemic naloxone resulted in a surge in plasma oxytocin compared to vehicle in the conscious rat. Naloxone in PVN both reversed and prevented OIRD by systemic fentanyl in the rat. Photostimulation of PVN oxytocin neurons prevented lethal effects of fentanyl OIRD, whereas dummy pulses failed to prevent lethal respiratory arrest in the mouse.

Conclusions:
Here, we confirm that naloxone stimulates oxytocin neurons of the PVN and results in a surge of plasma oxytocin. PVN opioid receptor antagonism and photoactivation of PVN oxytocin neurons are individually capable of reversing OIRD. Findings also indicate that PVN oxytocin neurons, previously unrecognized in reversal of OIRD, are a novel target for resuscitation agents.
Abstract 14459: Ten Year Evolving Profile of Black Americans With Myocardial Infarctions
Authors: Murillo Jaime , Ameli Omid , Henk Henry , Vojta Deneen
Published: April 2024

Background:
Racial disparities in the management and outcomes of myocardial infarction have been widely reported. Overall, the rate of cardiovascular (CV) death has risen since 2010 while hospitalization rates remain flat. Here, we provide a comprehensive analysis, using a large database, of the evolving profile of Black Americans (BA) who suffered myocardial infarctions (MI) over the past 10 years and compared BA to the non-Black (non-BA) population. We also describe the change in their characteristics between 2 continuous 5-year periods (2010-14, 2015- 19) with the goal of identifying opportunities for care improvement.

Methods:
We used the OptumLabs Data Warehouse EHR data. Acute MI cases were based on discharge diagnosis codes for adults
>
35 years of age between 1/1/2010 and 12/31/2019. A single individual could have had multiple MI’s. Data were analyzed descriptively.

Results:
A total of 36M annual observations were analyzed which included 129,146 MI’s with complete EHR data. MI’s among BA patients comprised 8.7% of the total in the 1
st
period and went up to 10.4% in the 2
nd
period.The main characteristics between BA and non-BA cases and between periods are shown in the table. In general, BA MI patients were younger than non-BA (57% vs 40% were <65).

Conclusion:
Compared to non-Blacks, Black patients with myocardial infarctions over the past 10 years exhibit a profile characterized by: MI’s at a younger age, almost half female, more DM, higher cholesterol and blood pressure levels, higher rate of smoking, more are Medicaid and ¾ live in the South.When comparing only Black patients between 2010-14 and 2015-2019 there was a marked increase in total MI’s, mostly in the 55-75 age range, increased diabetes, smoking and rising SBP levels.The description of an evolving profile among Blacks with MI’s could, at least partly, explain the rising trend of CV mortality, identify potential gaps in care and the need to design new forms to detect subclinical atherosclerosis.
Abstract 6919: Comparative Effectiveness of Long-Acting Insulin Analogs and Neutral Protamine Hagedorn (nph) Insulin for the Reduction of Major Adverse Cardiovascular Events Among Patients With Type 2 Diabetes
Authors: Brunetti Vanessa C C , Yu Oriana H , Platt Robert W , Filion Kristian B
Published: April 2024

Introduction:
Although long-acting insulin analogs (glargine, detemir, and degludec) and neutral protamine Hagedorn (NPH) insulin show similar efficacy for glycemic control among patients with type 2 diabetes, their comparative effectiveness in reducing cardiovascular events is unclear.

Objective:
To compare the risk of major adverse cardiovascular events (MACE) with the use of long-acting insulin analogs versus NPH among patients with type 2 diabetes.

Methods:
We conducted a retrospective cohort study using the Clinical Practice Research Datalink, a primary care database from the United Kingdom, linked with hospitalization and vital statistics data. The cohort included adults with type 2 diabetes initiating basal insulin therapy between 2002 and 2018. Exposure was defined as time-varying where each person-month of follow-up was classified as either current use of long-acting insulin analogs or NPH; patients who discontinued insulin treatment or were exposed to both insulin analogs and NPH in the same month were censored. The primary endpoint was MACE, a composite endpoint of myocardial infarction, ischemic stroke, and cardiovascular death. We used inverse probability of treatment and censoring weighting to estimate the adjusted hazard ratio (HR) and 95% confidence interval (CI) for MACE associated with current use of long-acting insulin analogs versus NPH. We also conducted secondary analyses stratified by age, sex, history of cardiovascular disease .

Results:
A total of 57,334 patients entered our cohort (31,136 using a long-acting analog and 26,198 using NPH. Mean age was 63.8 years, and 44.3% of patients were female. A total of 3,494 MACE events occurred over a mean follow-up of 1.62 years. Long-acting insulin analogs were not associated with a decreased risk of MACE compared to NPH (Table).

Conclusions:
Current use of long-acting insulin analogs is not associated with a reduced risk of MACE compared to use of NPH insulin among patients with type 2 diabetes.
Abstract 6932: Safety of Left Atrial Appendage Closure on Uninterrupted Warfarin Therapy
Authors: Yoo David , Gibson Spencer , Price Matthew J , Natale Andrea , Horton Rodney , Reddy Vivek Y , Doshi Shephal , Holmes David R , Kar Saibal , gibson douglas
Published: April 2024

Introduction:
Left atrial appendage closure (LAAC) device for stroke prevention is a safe and effective alternative to oral anticoagulation (OAC) in patients with atrial fibrillation (AF). The safety of performing LAAC on uninterrupted warfarin (UW) compared to interrupted warfarin (IW) is currently unknown.

Hypothesis:
Complication rates of performing LAAC on UW vs. IW will be similar.

Methods:
We reviewed the data from the second half of PROTECT-AF trial, PREVAIL trial, CAP and CAP2 registries. Patients were categorized to the UW group if INR on the day of the procedure was ≥2 and to the IW group if INR was <2. Procedural complications within 7 days of LAAC were reviewed. An association between complications and AC strategy was analyzed.

Results:
Data from 1580 patients were reviewed and 294 patients (18.6%) received LAAC on UW. The UW group had a mean INR of 2.4±0.4 and IW group had a mean INR of 1.3±0.3. There were several differences in baseline characteristics: lower BMI in the UW group (28.6±5.3 vs 29.5±6.0, p=0.01), fewer patients with hypertension in the UW group (87.1% vs 91.1%, p=0.04), lower HAS-BLED score in the UW group (2.0±1.0 vs 2.1±1.0, p<0.01), and more patients with persistent AF in the UW group (37.1% vs 26.4%, p<0.01). Overall, there were no significant differences in total or individual complication rates between the two groups (UW 5.1% vs IW 6.1%, p=0.59). Although not statistically significant, lower event rates were noted in the UW group for the following: stroke (0% vs 0.3%, p>0.99), pericardial effusion requiring intervention (1.7% vs 1.8%, p>0.99), pseudoaneurysm (0% vs 0.4%, p=0.59), hematoma (0% vs 0.2%, p>0.99), and device embolism (0% vs 0.2%, p=1.0). The UW group had statistically insignificant higher events rates of AV fistula (0.3% vs 0%, p=0.19) and major bleeding requiring transfusion (1% vs 0.5%, p=0.38). In addition, there was no significant difference in periprocedural ischemic stroke (0% vs 0.3%, p>0.99).

Conclusion:
In this retrospective analysis, no significant difference was observed in procedural complication rates when performing LAAC on UW vs. IW. These results suggest that LAAC can be safely performed without interruption of OAC.
Abstract 8889: Predictors of 30-Day Readmission in Nonagenarians Presenting With Acute Diastolic Heart Failure: Nationwide Analysis
Authors: Maraey Ahmed , Elsharnoby Hadeer , Elzanaty Ahmed , Younes Ahmed , Khalil Mahmoud , Salem Mahmoud , Dawoud Nabila
Published: April 2024

Background:
Acute diastolic heart failure (DHF) is a common but poorly studied diagnosis in hospitalized nonagenarians.

Objective:
To identify predictors of 30-day readmission in nonagenarians hospitalized with acute DHF.

Methods:
We queried National Readmission Database (NRD) of years 2016-2018 for patients aged 90 or above admitted with acute or acute on chronic DHF. ICD-10 was used to identify diagnoses. We excluded patients discharged in December and those who died in index admission. Univariate regression was performed on each variable. Variables with p value of < 0.2 were included in our multivariate regression model (figure 1).

Results:
From a total of 45393 index admissions, 43646 (96.2%) survived to discharge. A total of 7437 (16.4%) patients had a 30-day readmission. Mean cost of readmission was 43265 USD per patient. Significant predictors of 30-day readmission were chronic ischemic heart disease (OR=1.11, 95%CI [1.01-1.22], P=0.023), chronic kidney disease stage 3 or above (OR=1.19, 95%CI [1.07-1.34], P=0.002), complicated diabetes (OR=1.22, 95%CI [1.07-1.38], P=0.003), and length of stay (LOS) > 2 days (OR=1.20, 95% CI [1.09-1.32], P=0.000). Female sex (OR=0.90, 95% CI [0.83-0.99], P=0.030) and palliative care visit (OR=0.27, 95% CI [0.21-0.34], P=0.000) were associated with lower odds of readmission.

Conclusion:
In nonagenarians hospitalized with acute DHF, 30-day readmission is common and costly. Chronic comorbidities and LOS >2 days were predictors of readmission. Palliative care visit was strongly associated with lower risk of readmission. Further strategies need to be developed to improve the quality of care and prevent readmission in this age group.
Abstract 9055: Vascular Age in Patients With Familial Hypercholesterolemia and/or Elevated Lipoprotein(a) Treated With Lipoprotein Apheresis
Authors: Safarova Maya S , Gorby Lauryn , Nugent Anne , Dutton Julie-Ann , Moriarty Patrick M
Published: April 2024

Introduction:
The 2020 ASE guidelines indicate that an average mean carotid intima-media thickness (CIMT) ≥75th percentile for the patient’s age, sex, race/ethnicity is indicative of increased risk of atherosclerotic cardiovascular disease (ASCVD). With each 10 μm/year reduction of CIMT progression there is a relative risk reduction in the ASCVD event rate by 9% (95% confidence interval, 0.87-0.94). Published nomograms of CIMT percentiles determine “vascular age,” defined as the age at which the composite CIMT value for an individual would represent the median value.

Hypothesis:
Lipid-modifying treatment with lipoprotein apheresis (LA) over the course of 10 years will affect vascular age in patients with baseline elevated CIMT due to severe hypercholesterolemia.

Methods:
Ten individuals (mean age 60±9 years, 70% female) with familial hypercholesterolemia and/or elevated lipoprotein(a) [Lp(a)] were treated every two weeks with LA (Liposorber, Kaneka, Japan) between 2005 and 2020 (median duration, 12 years).

Results:
Acute effects of LA included reduction in LDL-C and Lp(a) levels by a median of 72±8% and 75±7%, respectively. The proportion of patients with average mean CIMT ≥75th percentile was 8/10 at the time of apheresis initiation. LA resulted in mean CIMT reduction of –40μm (IQR, –50 to 20). This translated into 70% (7/10) of cases demonstrating composite mean CIMT below their expected vascular age. The follow-up mean CIMT strongly correlated only with the baseline Lp(a) levels. The number of patients with CIMT above their “vascular age” decreased from 80% to 30% over treatment course. The rate of ASCVD was 37.5 per 1000 person-years while on LA.

Conclusions:
While annual CIMT progression rates average 15 μm/y, an increase in CIMT seen with advanced age and severe hypercholesterolemia was halted with LA with an estimated annual rate of change in mean common CIMT of –4 μm/y and maximum CIMT of –3μm /y. This analysis demonstrates positive impact of LA on vascular age.
Abstract 9057: Anti-inflammatory Effect of Biologic Therapy in Patients With Psoriatic Disease: A Prospective Cohort Fdg-pet Study
Authors: Boczar Kevin E , Glassman Steven , Wang Jerry , zeng wanzhen , deKemp Robert , Ward Natalie , Beanlands Rob S , Fehlmann Christophe A , Wells George , Karsh Jacob , Dwivedi Girish
Published: April 2024

Introduction:
Psoriatic arthritis (PsA) and cutaneous psoriasis (PsO) are linked with an increased risk of adverse cardiovascular events.

Hypothesis:
Central vascular inflammation (VI) as measured on F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in the ascending aorta will improve in patients following therapy with biologic agents compared to PsO patients receiving non-biologic therapy and controls. We also postulate that in patients responding to biologics, there will be an improvement in coronary microvascular dysfunction as measured by myocardial blood flow reserve (MFR) determined by rubidium-82 (82Rb) PET.

Methods:
We studied 3 patient cohorts (patients with PsA and/or PsO started on biologic agents, patients with PsO managed on non-biologic therapy, and patients with non-inflammatory arthritis). The primary outcome of our study was the change in VI, estimated as the target-to-background ratio by FDG PET in the most diseased segment of the ascending aorta at baseline compared to 6-month follow-up (TBRmax). We also performed 82Rb PET studies at baseline and 6-month follow-up to determine any changes on left ventricular MFR.

Results:
34 participants were enrolled in the study (11 PsA and/or PsO patients on biologic agents, 13 patients in PsO group managed on non-biologic therapy, and 10 in the non-inflammatory control group). A significant drop in the thoracic aorta uptake was observed in the biologic-treated group (change in TBRmax: -0.46±0.55) when compared to the the PsO group treated with non-biologic therapy (change in TBRmax: 0.23±0.67). The group with imaging evidence of a response to biologic agents (i.e. TBRmax drop greater than median value) maintained MFR (change in MFR of 0.05±0.19) when compared to the group with a response on TBRmax that was below the median, which had a drop in MFR (-2.9±0.8) (P=0.03).

Conclusions:
VI in the thoracic aorta decreased compared to psoriasis patients treated with non-systemic therapies and controls. Psoriasis patients treated with biologics who demonstrated a significant response on FDG PET imaging, maintained their MFR compared to non-responders. There is a positive impact of immune therapies on VI and microvascular disease in patients with chronic inflammation.
Abstract 9061: Aortic Wall Stress Across Risk Groupings of Aortic Size and Height Indices in a Male Veteran Population With Ascending Thoracic Aortic Aneurysm
Authors: Zamirpour Siavash , Xuan Yue , Wang Zhongjie , Gomez Axel , Hope Michael D , Leach Joseph , Saloner David A , Guccione Julius M , Ge Liang , Tseng Elaine E
Published: April 2024

Introduction:
Natural history studies of ascending thoracic aortic aneurysm (aTAA) identified maximum diameter as a predictor of aortic dissection, informing guidelines for prophylactic surgery. Studies have since challenged the biomechanical basis of diameter-based risk assessment. Indices of diameter with measures of body size were proposed to account for individual variation in diameter, including body surface area as aortic size index (ASI) or height as aortic height index (AHI). The goal of this study was to determine differences in aneurysm wall stresses across previously defined clinical risk groups for ASI and AHI.

Methods:
Height and weight measurements were retrospectively reviewed for 264 male veterans with aTAA. Wall stresses were previously simulated using finite element analyses on patient-specific geometries. Group differences in wall stress were assessed among ASI and AHI risk groups using the Kruskal-Wallis and Dunn tests.

Results:
Median ± interquartile range circumferential stresses among ASI risk groups were 486.5 ± 132.8, 510.7 ± 140.5, and 617.2 ± 201.6 kPa for groups 1-3 (
P
= .19). Longitudinal stresses were 307.3 ± 70.8, 300.8 ± 67.9, and 359.1 ± 57.2 kPa (
P
= .09). Among AHI risk groups, circumferential stresses were 476.9 ± 151.4, 503.3 ± 135.4, and 586.2 ± 102.6 kPa for groups 1-3 (
P
= .008). Longitudinal stresses were 297.6 ± 80.7, 304.1 ± 64.7, and 361.2 ± 122.9 kPa (
P
= .004). For both circumferential and longitudinal stresses, pairwise comparisons were significant between groups 1,3 and 2,3. No observations were classified as group 4 for ASI or AHI.

Conclusions:
Differences in wall stress were not significant across ASI risk groups and were significant between AHI groups 1,3 and 2,3. While both indices have been shown to stratify clinical outcomes, AHI-based risk groups may better reflect differences in biomechanical state. Prospective studies may further elucidate the relationship between biomechanical status and clinical outcomes.