bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13292: Bradycardia as a Manifestation of Chikungunya Myocarditis. A New Threat to America
Authors: Gonzalez Carta Karina A , Mendoza_Britto Ivan J , Finizola Vicente , Morr Igor , Torres Jaime , Meza Yolimar , Marquez Juan , Villalobos Iris , Vasquez Rosalyn , Chazzim Gerardo , Morr Claudia , Morr Carlos , Mendoza Ivan J
Published: April 2024

Background:
Chikungunya fever is an arthropod-borne disease that has caused millions of infections globally. Local transmission has been reported in the United States. There are very few published reports concerning the cardiac complications in general and bradycardia in particular.

Objective:
To investigate the occurrence of myocarditis and bradycardia in patients with Chikungunya fever.

Methods:
Prospective multicenter observational studio of 287 patients with a chikungunya infection during a Venezuelan outbreak. Clinical evaluation, X Ray, ECG, Echocardiogram, Holter, laboratory including virological evaluation, cardiac biomarkers, and cardiac MRI procedures were performed.

Results:
Of the 287 patients examined, 117 were male with a mean age of 59 ± 8; 277 patients presented with fever and polyarthralgia and 91 developed palpitations. Arrhythmias occurred in 45% of cases; they included bradiarrhytmias (33%), atrial and ventricular ectopic beats and tachyarrhythmia’s in which atrial fibrillation was observed in 19 cases. There were also ectopic atrial tachycardia and non-sustained ventricular tachycardia, conduction disturbances and 3 cases of sudden death.

Conclusion:
Physicians should be aware of the possibility of manifest or silent myocarditis in almost half of patients with Chikungunya disease. In a proper epidemiological context, the triad of fever, polyarthralgia and new arrhythmia, including bradiarrhytmias suggests Chikungunya myocarditis.
Abstract 13412: Differential Insulin-dependent Signaling Pathways Modulated by Hydrogen Peroxide in Cardiac Myocytes
Authors: Steinhorn Benjamin , Sartoretto Juliano , Kalwa Hermann , Romero Natalia , Abel E. D , Michel Thomas
Published: April 2024

Hydrogen peroxide (H
2
O
2
) has long been implicated in insulin signal transduction, yet the mechanisms whereby insulin regulates intracellular H
2
O
2
to modulate physiological responses remain obscure. Here we explore the roles of H
2
O
2
in regulation of insulin pathways in cardiac myocytes. We found that insulin inhibits cardiac myocyte beta adrenergic physiological and biochemical responses. We found that catalase (which degrades H
2
O
2
) completely blocks the ability of insulin to activate the insulin-responsive kinases Akt/mTOR and also to attenuate beta adrenergic receptor-mediated increases in myocyte contractility. These insulin responses are abrogated in a mouse model of type 2 diabetes, establishing a key role for H
2
O
2
-dependent pathways in the diabetic heart. To directly probe intracellular H
2
O
2
responses to insulin in cardiac myocytes, we constructed a novel recombinant AAV9 vector expressing the fluorescent H
2
O
2
biosensor HyPer, which we used to infect mice
in vivo
. We isolated cardiac myocytes from mice infected with this biosensor and performed quantitative imaging studies. This approach revealed robust insulin-dependent increases in cardiac myocyte H
2
O
2
in response to insulin in wild-type mice. Attenuated H
2
O
2
responses were observed in myocytes isolated from mouse lines deficient in the NADPH oxidase isoforms Nox2 or Nox4 that had been infected with HyPer-AAV9. In Nox2 knockout myocytes, we found that insulin-promoted phosphorylation of kinases Akt and mTor is markedly attenuated, while insulin-dependent inhibition of beta adrenergic contractility is unaffected. In contrast, in cardiac myocytes isolated from the Nox4 knockout mouse, insulin-dependent Akt/mTor phosphorylation responses are unaffected, while the ability of insulin to attenuate the beta adrenergic increase in myocyte contractility was lost. These studies represent an important advance in our understanding of insulin action in the heart by identifying a proximal point of bifurcation in insulin signaling via the differential activation of two NADPH oxidase isoforms. The work also provides insight into mechanisms of diabetic cardiomyopathy, and suggest that insulin resistance in the diabetic heart may unmask potentially deleterious beta adrenergic responses.
Abstract 13423: Sleep Disruption is Associated With Incident Atrial Fibrillation Independent of Obstructive Sleep Apnea
Authors: Christensen Matthew A , Dixit Shalini , Whitman Isaac R , Nah Gregory , Dewland Thomas A , Vittinghoff Eric , Mukamal Kenneth J , Redline Susan , Robbins John A , Newman Anne B , Patel Sanjay R , Magnani Jared W , Psaty Bruce M , Heckbert Susan R , Olgin Jeffrey E , Pletcher Mark J , Marcus Gregory M
Published: April 2024

Introduction:
Obstructive sleep apnea (OSA) is an established risk factor for atrial fibrillation (AF), but the mechanism is unknown. Repeated hypopneas may induce mechanical stress but OSA also causes poor sleep which has been linked to other CVD. We sought to determine if sleep disruption independent of OSA is associated with AF.

Methods:
We compared sleep quality to AF in three population-based cohorts. (1) In the Health eHeart Study (HeH), an internet-based cohort study, we compared self-reported frequent nighttime awakening (waking at night ≥ 3x / week) to prevalent AF using logistic regression. (2) In the Cardiovascular Health Study, (CHS) we used Cox proportional hazards models to assess self-reported frequent nighttime awakening at baseline as a predictor of incident AF. (3) Last, we used statewide medical records in the California Healthcare Cost and Utilization Project (C-HCUP) from 2005 to 2009 to compare the diagnosis of insomnia to incident AF, again with Cox proportional hazards models.

Results:
Sleep disruption was associated with prevalent AF (HeH) and incident AF (CHS, C-HCUP) before and after adjustment for OSA and other potential confounders (
Figure
). (1) In HeH, 553/4603 (12%) had AF, and frequent nighttime awakening was associated with increased odds of AF. (2) In CHS, over a median 11.6 years (IQR 6.2 - 16.4) of follow-up 1593 (28%) developed AF; frequent nighttime awakening was associated with increased risk of incident AF. (3) Among 13,967,949 patients in C-HCUP over the 5-year study period, of which 375,318 (3%) developed AF over a median of 3.8 years (IQR 1.8 - 4.3), insomnia was associated with an increased risk of incident AF.

Conclusions:
Sleep disruption was associated with an increased risk of prevalent and incident AF after adjustment for OSA and other confounders in 3 diverse cohorts. Factors inherent to sleep may be important in AF pathogenesis and sleep quality may therefore be a modifiable risk factor for AF.
Abstract 13451: Oxldl-derived Lysophosphatidic Acid Generates a Nf-κB Signature Through Lpar1 That Promotes the Progression of Aortic Valve Stenosis
Authors: Nsaibia Mohamed J , Boulanger Marie C , Mkannez Ghada , Bouchareb Rihab , Bossé Yohan , Pibarot Philippe , Arsenault Benoît , Marette André , Mathieu Patrick
Published: April 2024

Background:
Mendelian randomization studies have revealed an association between low-density lipoprotein (LDL) and calcific aortic valve stenosis (CAVS). Circulating level of oxidized phospholipids, a component of oxidized LDL (OxLDL), is associated with the progression rate of CAVS. Autotaxin (ATX) is a lysophospholipase D enzyme that transforms lysophosphatidylcholine (LPC), into lysophosphatidic acid (LPA). Recently, we demonstrated that LPA, which is generated by ATX, was present in the aortic valve and was an important driver of aortic valve mineralization. However, the process whereby oxidatively transformed LDL promotes the development/progression of CAVS is largely unknown.

Objective:
We aimed to examine the molecular processes whereby OxLDL promotes the mineralization of the aortic valve and the progression of CAVS.

Methods:
We documented the expression of LPA receptor 1 (LPAR1) in explanted CAVS and in control non-mineralized aortic valves. Effects of OxLDL-LPA on osteoblastic differentiation of cultured valve interstitial cells (VICs) were investigated by using promoter luciferase assay and RT-qPCR analysis for the osteoblastic markers.

Results:
We found that autotaxin (ATX), a lysophospholipase D, is transported by the LDL fraction. Upon oxidation of LDL, LPA is generated through the activity of ATX, promoting a strong osteogenic activity in VICs. In-depth functional assays showed that OxLDL/LPA-mediated osteogenic activity in VICs relied on LPAR1 and phosphorylation of p65 on serine 536, which is recruited to the promoter of bone morphogenetic protein 2 (
BMP2
). In human and mouse mineralized aortic valves, the expression of LPAR1 is increased. In obese diabetic LDLR
-/-
/ApoB
100/100
/IGFII transgenic mice (IGFII), the development of CAVS was associated with a rise of circulating LPA, which correlated with the plasma ATX activity and cholesterol level. In this murine model of an established CAVS, inhibition of LPAR1 with Ki16425 decreased the progression rate of CAVS by 3.0-fold.

Conclusion:
These findings indicate that OxLDL-mediated progression of CAVS is promoted by LPA driving an inflammatory pathway that promotes the osteogenic activity of VICs. LPAR1 may thus constitute a novel target to prevent the progression of CAVS.
Abstract 13799: Loperamide; An Old Drug With Deadly New Consequences
Authors: Abdelrahman Mohamed , Jones Clayton , Storm Randle , Zazzali Kathleen , Al-Azizi Karim , Oren Jess
Published: April 2024

Introduction:
Loperamide is an over the counter (OTC) opioid-like antidiarrheal originally presumed to lack central nervous system effects, however recent reports have shown that, at supra-therapeutic doses, loperamide can cross the Blood Brain barrier and have opioid-like effect. In this case series we review the clinical course of two patients with life-threatening arrhythmia secondary to loperamide abuse.

Case One:
A 37 year old female with congenital long QT syndrome (LQTS) presented to the emergency room (ER) with syncope; monitoring revealed incessant Torsades des Points (TdP); QTc was 678 msec on 12-lead EKG and electrolytes were normal, and drug screen was negative. She admitted to taking up to 120mg/day of loperamide recently for relief of chronic back pain. Acutely she was administered intravenous magnesium and admitted to the hospital; and over the following six days her QTc gradually trended down to 478 msec (similar to baseline) at which point she was discharged.

Case Two:
A 24 year old male with LQTS presented with an episode of TdP during tooth extraction, and continued to have TdP in the ER. He had received anti-emetics (known to cause QT prolongation) prior to his tooth extraction, but also admitted to taking up to 200mg/day of loperamide over the past 1-2 months. In the setting of a modestly prolonged QTc (520 msec), he continued to have TdP refractory to magnesium and required trans-venous overdrive pacing to suppress the arrhythmia over the following 48 hours. He eventually stabilized, and was discharged on hospital day five with a QTc of 474 msec.

Discussion:
Referred to as “poor man’s methadone", loperamide has been available OTC since 1988. It is inexpensive (circa $10 for 400 2mg tablets) and universally available, leading to increasing frequency of abuse. It may not be detected on routine drug screening, but its abuse should still be considered in patients with TdP or prolonged QT interval.
Abstract 13801: Cardiopulmonary Bypass is Protective Against Shunt Thrombosis in Patients Undergoing Placement of Modified Blalock-Taussig Shunt
Authors: Patregnani Jason T , Sochet Anthony A , Klugman Darren , Diab Yaser , Berger John , Sinha Pranav
Published: April 2024

Introduction:
Enhancements in surgical technique and cardiopulmonary bypass (CPB) technology have contributed to dramatically improved outcomes of staged palliation for single ventricle patients. However, in-hospital mortality after first stage palliation procedures remains high at 16%. Systemic to pulmonary artery shunt (SPS) thrombosis is a major contributor to morbidity in these patients with an incidence reported between 5 to 37%. Cardiopulmonary bypass is known to have hypocoagulable sequelae.

Hypothesis:
Hypocoagulable sequelae of CPB are protective against early thrombosis of systemic to pulmonary artery shunts.

Methods:
We performed a retrospective cohort study from January 2008 through December 2014 of all children undergoing single ventricle palliation with a SPS. Early shunt thrombosis was defined as clinical hypoxemia necessitating cardiac catheterization, with angiographic evidence of a thrombosis within the shunt during the same admission. Cohorts with and without early shunt thrombosis and those with and without CPB were compared using Wilcoxon sign rank sum test, Student’s t-test and Fisher’s exact test as appropriate. Unadjusted logistic regression was used to assess independent predictors for development of shunt thrombosis.

Results:
Within the study period a total of 75 neonates underwent placement of SPS (with CPB n = 25, without CPB n = 50) with an operative mortality of 11%( 8/75). In this cohort, 12% (9/75) patients developed an early shunt thrombosis during the index admission. All instances of shunt thrombosis were observed in cases performed without CPB (without CPB n = 9; with CPB n =0) (p = 0.03). Unadjusted logistic regression of CPB on early shunt thrombosis yielded an odds ratio of 0.14 (95% CI: 0.01-0.93,
p
= 0.04).

Conclusions:
Patient’s undergoing SPS placement without CPB have an increased incidence of shunt thrombosis as compared to those with CPB. Additional studies to understand the hypocoagulable sequelae of CPB are required and may help in preventing shunt thrombosis in patients undergoing SPS.
Abstract 13824: Oral Anticoagulants and Risk of Liver Injury in Patients With Atrial Fibrillation: A Prospective Study
Authors: Alonso Alvaro , MacLehose Richard F , Chen Lin Y , Bengtson Lindsay G , Chamberlain Alanna M , Norby Faye L , Lutsey Pamela L
Published: April 2024

Introduction:
Isolated cases of liver injury associated with the use of non-vitamin K antagonist oral anticoagulants (NOACs) have been reported. However, the comparative incidence of liver injury in users of different oral anticoagulants is unknown.

Methods:
We studied 113,717 patients (mean age 70, 39% women) with non-valvular atrial fibrillation (AF) included in the MarketScan® Commercial and Medicare Supplemental databases with a first prescription for oral anticoagulation after November 4, 2011, followed through December 31, 2014. Of these, 56,879 initiated warfarin, 17,286 initiated dabigatran, 30,347 initiated rivaroxaban, and 9,205 initiated apixaban. Liver injury hospitalizations were identified using selected inpatient diagnostic codes. Multivariable Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of liver injury by anticoagulant type.

Results:
During a median follow-up of 12 months, 960 hospitalizations with liver injury were identified. Rates of liver injury hospitalization (per 1000 person-years) by oral anticoagulant were 9.0 (warfarin), 4.0 (dabigatran), 6.6 (rivaroxaban), and 5.6 (apixaban). After multivariable adjustment, rates of liver injury hospitalization were lower in initiators of NOACs compared to warfarin: HR (95%CI) of 0.57 (0.46, 0.71), 0.88 (0.75, 1.03) and 0.70 (0.50, 0.97) for initiators of dabigatran, rivaroxaban, and apixaban, respectively (Table). Compared to dabigatran initiators, rivaroxaban initiators had a 56% increased risk of liver injury hospitalization (HR 1.56, 95%CI 1.22, 1.99). In addition to type of anticoagulant, prior liver, gallbladder, and kidney disease, cancer, anemia, heart failure, and alcoholism significantly predicted liver injury hospitalization.

Conclusions:
Among patients with non-valvular AF, NOACs were associated with lower risk of liver injury hospitalization compared to warfarin, with dabigatran showing the lowest risk.
Abstract 13839: Differences in Prevalence, Incidence, and Progression of Coronary Artery Calcium among Participants With Chronic Kidney Disease With and Without Diabetes Mellitus: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Shroff Gautam R , Sanchez Otto A , Miedema Michael D , Kramer Holly , Ix Joachim H , Duprez Daniel A , Jacobs David R
Published: April 2024

Introduction:
Chronic kidney disease (CKD) is associated with elevated coronary artery calcium (CAC) scores, presumed from altered calcium/phosphorus metabolism. However, differences in prevalence/progression of CAC in CKD with (CKD-DM) and without (CKD-non-DM) diabetes are not known.

Methods:
The MESA cohort (6780 individuals aged 45-84 yr, with no clinical cardiovascular disease enrolled 2000-02) were followed until 2010-12. Baseline CKD was identified (eGFR<60 ml/min/1.73 m
2
using CKD-EPI creatinine and cystatin C-based eGFR or spot urine albumin/creatinine ≥ 17 mg/g in men; 25 mg/g in women). Prevalent CAC was defined by baseline Agatston score >0, incident CAC by any follow-up Agatston score > 0 in those with baseline CAC=0, and CAC progression by any CAC score increase vs. baseline. CAC progression was adjusted for demographic, clinical and inflammatory biomarker variables using linear regression.

Results:
1308 (19.3%) MESA participants had CKD, while 853 (12.5%) had DM. CAC > 0 at baseline was lowest (44.3%) in non-CKD, non-DM, intermediate in those with either condition, and highest (67.1%) in CKD-DM participants (table). CAC incidence (among those with CAC=0 at baseline) was highest in CKD-DM, lowest in non-CKD-non-DM (39.3% vs 18.3%, p<0.0001) & intermediate with either CKD or DM alone (27%). About 90% of those with CAC > 0 at baseline had an increase in Agatston score in follow-up; Agatston score increased 37.0/yr in non-CKD-non-DM, 57.6/yr in CKD-non-DM, 68.3/yr in non-CKD-DM, and 107.6/yr in CKD-DM (all pairwise p<0.001). Extensive adjustment (table) attenuated to similar increases between non-CKD-non-DM and CKD-non-DM (40.6 vs 47.2/yr, p=0.09). Greater increases remained in non-CKD-DM (65.7/yr) and in CKD-DM (95.8/yr, p<0.002).

Conclusion:
CKD-non-DM participants had slower CAC incidence/progression compared to CKD-DM participants. CAC differences among CKD participants may help identify subgroups at higher risk of future events.
Abstract 13881: Determining Factors and Prognostic Value of Plasma γ- Atrial Natriuretic Peptide Ratio in Patients With Heart Failure
Authors: Takashio Seiji , Takahama Hiroyuki , Hayashi Tomohiro , Nagai-Okatani, Chiaki , Nishikimi Toshio , Nakagawa Yasuaki , Amaki Makoto , Ohara Takahiro , Hasegawa Takuya , Sugano Yasuo , Kanzaki Hideaki , Yasuda Satoshi , Kangawa Kenji , Minamino Naoto , Anzai Toshihisa
Published: April 2024

Background:
Atrial natriuretic peptide (ANP) is a peptide hormone that maintain sodium homeostasis and inhibit activation of the renin-angiotensin-aldosterone system. Three endogenous molecular forms of human ANP, including fully bioactive α-ANP, β-ANP; an antiparallel dimer of α-ANP, and γ-ANP; α-ANP precursor, are present in heart and plasma of patients with heart failure (HF). However, the clinical importance of molecular ratio of ANP has not been evaluated. This study was designed to evaluate plasma γ-ANP and total amount of ANP levels (total ANP) in patients HF, and identify the determining factor and prognostic value of %γ-ANP (γ-ANP /total ANP ratio).

Method and Results:
We prospectively evaluated plasma γ-ANP and total ANP levels in 148 patients with acute decompensated HF before discharge using by chemiluminescence enzyme immunoassay. Median plasma total ANP and γ-ANP levels were 142.5 [63.2-231.3] and 10.9 [4.4-25.6] pmol/ml, respectively. %γ-ANP was 8.9 [5.5-15.2]% and significantly correlated with age (ρ=0.205; p=0.01), body mass index (BMI) (ρ=-0.316; p<0.001), left ventricular ejection fraction (LVEF) (ρ=-0.250; p=0.002), hemoglobin (ρ=-0.182; p=0.03), and B-type natriuretic peptide (BNP) levels (ρ=0.393; p<0.002). Patients with high %γ-ANP (≥ median value) were more likely to have ischemic etiology and prior HF hospitalization history. High %γ-ANP tended to increase all cause death (p=0.06) and was significantly associated with repeat HF-related hospitalization (p=0.01;
Figure
).

Conclusion:
Increase of %γ-ANP was associated with older age, lower BMI, LVEF hemoglobin, and higher BNP levels. High %γ-ANP was a predictor of future HF-related rehospitalization. These results suggested that %γ-ANP was affected by presence of known poor prognostic factors of HF.
Abstract 13894: Prediction of Mode of Death by Model of End-Stage Liver Disease Excluding INR (MELD-XI) Scoring System in Patients Admitted for Acute Decompensated Heart Failure With Preserved and Reduced Ejection Fraction; a Comparison With Nonalcoholic Fatty Liver Disease Fibrosis Score
Authors: Yamada Takahisa , Morita Takashi , Furukawa Yoshihiro , Tamaki Shunsuke , Iwasaki Yusuke , Kawasaki Masato , Kikuchi Atsushi , Kondo Takumi , Ozaki Tatsuhisa , Seo Masahiro , Sato Yoshihiro , Ikeda Iyo , Fukuhara Eiji , Abe Makoto , Nakamura Jun , Fukunami Masatake
Published: April 2024

Backgrounds:
Cardiohepatic interactions have been a focus of attention among heart failure. A model of end-stage liver disease excluding INR (MELD-XI), a robust scoring system of liver dysfunction, has been shown to provide prognostic information in heart failure patients (pts). Furthermore, it was reported that nonalcoholic fatty liver disease (NAFLD) is a risk factor for cardiovascular disease. There is a difference in mode of death (cardiac vs non-cardiac death) between heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF). We sought to investigate the prognostic significance of MELD-XI and NAFLD in the prediction of mode of death in pts admitted for acute decompensated heart failure (ADHF), relating to HFpEF and HFrEF.

Methods and Results:
We studied 303 consecutive ADHF pts (HFrEF[LVEF<50%]; n=163, HFpEF[LVEF≥50%];n=140). MELD-XI score was calculated by the formula: 5.11х ln(bilirubin)+11.79х ln(creatinine)+9.44. NAFLD fibrosis score (NFS) was obtained by the formula: -1.675 + 0.037 х age + 0.094 х BMI + 1.13 х hyperglycemia or diabetes (yes = 1, no = 0) + 0.99 х AST/ALT - 0.013 х platelet ( х 10
9
/L) - 0.66 х albumin. During a follow-up period of 5.1±4.3 yrs, 65 pts had cardiac death and 56 pts had non-cardiac death. At multivariate Cox analysis, MELD-XI score, but not NFS, was significantly associated with cardiac death independently of prior heart failure hospitalization, BMI, systolic blood pressure and serum sodium level, while neither MELD-XI score nor NFS showed the association with non-cardiac death. MELD-XI of 13 was a fair discriminator for cardiac death (AUC 0.737[0.670-0.805]). In both groups with HFrEF and HFpEF, pts with higher MELD-XI score had a significantly higher risk of cardiac death than those with lower MELD-XI score.

Conclusion:
A MELD-XI scoring system might predict cardiac death but not non-cardiac death in ADHF pts, regardless of HFrEF or HFpEF, although NAFLD fibrosis score did not.
Abstract 16663: Child Health Promotion in Underserved Communities: Primary Results From the Cluster Randomized FAMILIA Trial
Authors: Fernandez-Jimenez Rodrigo , Jaslow Risa , Bansilal Sameer , Santana Maribel , Diaz-Munoz Raquel , Trabal Giselle , Latina Jacqueline , Soto Ana V , Vedanthan Rajesh , Giannarelli Chiara , Kovacic Jason , Bagiella Emilia , Kasarskis Andrew , Fayad Zahi , Hajjar Roger J , Fuster Valentin
Published: April 2024

Introduction:
Preschool-based interventions offer promise to instill healthy behaviors in children. However, its efficacy in underserved communities is not well established.

Objective:
To assess the impact of a preschool-based health promotion education intervention in an underserved community.

Methods:
We performed the cluster-randomized controlled “Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health” (FAMILIA) trial involving 15 Head Start preschools in Harlem, New York. Schools and their children were 3:2 randomized to either receive the usual curriculum (control); or a 4-month educational intervention for a total of 50 hours to instill healthy behaviors in relation to diet, physical activity, understanding how the human body and heart work, and emotion management. The primary outcome was the change from baseline in the overall knowledge, attitudes, and habits (KAH) score of the child. As secondary outcomes, we evaluated the changes in KAH subcomponents and in the test of emotion comprehension. Linear mixed-effects models were used to test for intervention effects.

Results:
We enrolled 562 children 3 to 5 years old, 51% female, 54% Hispanic/Latino and 37% African-American. The mean % relative change from baseline in the overall KAH score was 5.5% and 11.8% in control and intervention groups, respectively. The average between-group absolute difference in overall KAH was 2.89 points (95% CI: 0.61 to 5.17; p = 0.013; Figure). Physical activity and understanding of the human body and heart components, and knowledge and attitudes domains, were the main drivers of the effect. Changes in emotion comprehension trended to favor intervened children as compared to controls.

Conclusions:
The FAMILIA trial demonstrates that a multidimensional school-based education intervention is an effective strategy for instilling healthy behaviors among preschoolers from a diverse and socially/economically disadvantaged community. As part of our long-term vision, we are conducting a long-term follow-up of the children to assess the sustainability of the intervention effects.
Abstract 16680: Bioengineered Peptibodies as Novel Therapeutic Potassium Channel Blockers
Authors: Chidipi Bojjibabu , Cheng Mengmeng , Reiser Michelle , Teng Michael , Noujaim Sami F
Published: April 2024

Background:
Currently available antiarrhythmics are small molecules with limited safety and efficacy. Therefore, there is an increasing need for novel, safe, and potent ion channel blockers that can be used as antiarrhythmics. We thus bioengineered a peptibody, as a blocker of the acetylcholine activated inward rectifier potassium current (I
KACh
). I
KACh
has been postulated to play a role in chronic atrial fibrillation, making this potassium current a viable therapeutic target. The bioengineered peptibody was generated as a TertiapinQ- human IgG1 Fc fragment fusion protein. TertiapinQ is a 21 aminno acid blocker of I
KACh
isolated from the European honey bee venom. We hypothesized that the bioengineered peptibody is a more potent blocker of I
KACh
compared to TertiapinQ.

Methods:
We used conventional patch clamp, western blot, as well as whole animal electrophysiology to evaluate the effects of the peptibody on I
KACh
.

Results:
The peptibody was expressed in Expi293F cells, collected from the culture supernatant, and purified. Western blot showed the correct weight of the purified peptibody, at about 26 KDa. In patch clamp, the IC50s for block of I
KACh
with the peptibody was 20 pM, versus 10 nM for TertiapinQ. In mice injected i.p. with carbachol, which opens I
KACh
and slows down the heart rate, the peptibody delivered via jugular vein injection (50 μL of 1.3 μM) completely abrogated the bradycardic effects of carbachol, while TertiapinQ or the Fc fragment at the same concentration did not.

Conclusion:
We provide proof for the novel idea that anti-ion channels peptibodies can be powerful and highly potent ion channel blockers and have the potential to be developed into novel antiarrhythmic modalities.
Abstract 16894: Association Between Flow Mediated Vasodilation and Coronary Artery Disease
Authors: Shekar Chandana , Li Dong , Cherukuri Lavanya , Shaikh Kashif , Hamal Sajad , Birudaraju Divya , Shodhan Shivani , Nezarat Negin , Dailing Christopher , Flores Ferdinand , Roy Sion , Budoff Matthew
Published: April 2024

Introduction:
Flow-mediated vasodilatation rate (FMD) is an ultrasound measurement often used to assess vascular endothelial function. Endothelial dysfunction causes coronary atherosclerosis by decreasing nitric oxide levels, which alters vasodilation and causes destabilization of established plaque. Hence, FMD has been proposed to be a surrogate marker of atherosclerosis severity and predictive of cardiovascular outcomes.

Hypothesis:
We intend to evaluate the relationship between the severity of Coronary Artery Disease (CAD) and FMD. We hypothesize that patients with lower FMD would have more severe CAD when compared to individuals with higher FMD.

Methods:
We identified 291 patients (169 [58%] male, mean age 59.6 ± 11.3 years), clinically referred for Coronary Artery Calcium(CAC) Scoring and Coronary Computed Tomography Angiography (CCTA) at our center. After informed consent, we measured brachial artery FMD using ultrasound (UNEXEF, Unex, Japan). CAC was measured using Agatston method. Segment Involvement Score (SIS; the total number of segments with any plaque), Segment Stenosis Score (SSS; the sum of maximal stenosis score per segment), Total Plaque Score (TPS; the sum of all segments plaque burden) were assessed using the 17-segment model with CCTA. We calculated the median FMD. We used multivariate regression analysis to analyze the association between FMD and the markers of CAD (i.e., CAC, TPS, SSS, SIS), after adjusting for confounding variables.

Results:
Median FMD in the group was 4.1% (25%-75%: 2.2-6.0). After multivariable analysis, individuals with FMD lower than 4.1% were noted to have significantly higher CAC (p=0.024), TPS (0.024), SSS (p=0.015) and SIS (p=0.010). (Table 1)

Conclusions:
We conclude that impaired FMD rate is an indicator of more severe coronary artery disease. Further studies to evaluate non-invasive ultrasound FMD measurement as a tool for predicting subclinical atherosclerosis and mechanisms are warranted. This could also serve to provide additive information for risk stratification of patients and cardiovascular outcomes.
Abstract 16921: Noninvasive Quantification of Myocardial Elasticity in Patients With Hypertrophic Cardiomyopathy
Authors: Anupraiwan Orawan , Pislaru Sorin V , Pellikka Patricia A , Pislaru Cristina
Published: April 2024

Introduction:
Hypertrophic cardiomyopathy (HCM) is associated with excessive left ventricular (LV) hypertrophy (LVH), myocyte disarray and expansion of interstitial collagen. These factors alter mechanical properties of the myocardial tissue. Intrinsic velocity propagation (iVP) of myocardial stretch is a new validated measure of myocardial elasticity.

Hypothesis:
iVP in left ventricular (LV) myocardium of patients with HCM will be increased compared to normal subjects.

Methods:
We studied prospectively 100 subjects: 42 with HCM (age 57 ± 14 years; 79% with asymmetric septal LVH) and 58 normal controls without cardiovascular disease (age 48 ± 13 years). Patients had comprehensive transthoracic echocardiography and cardiac magnetic resonance imaging (MRI; n=29). iVP was measured throughout the LV myocardium during late diastole using ultra-high frame rate tissue Doppler imaging (350-460 fps) (6 LV walls, 3 standard apical views). Chamber stiffness (CS) was evaluated from end-diastolic pressure-volume relationship (EDPVR) estimated noninvasively by the single-beat method (EDP=αV
β
). End-diastolic pressure (EDP) was estimated from E/e’.

Results:
LV ejection fraction was normal in both groups (HCM: 68 ± 7%; Controls: 65 ± 5%). Myocardial stiffness by iVP was markedly higher in HCM vs. controls (Fig.A, left panel). This was confirmed by EDPVRs, which were steeper and shifted leftward (Fig. B, left). The slope (β, load-independent) of EDPVR and CS (dP/dV) were higher and LV capacitance (V
30
, estimated volume at 30 mmHg EDP) was lower in HCM (Fig. B, right) and correlated significantly, though weakly, with iVP (β: r = 0.41; CS dP/dV: r = 0.48; EDP: r = 0.61; p<0.002 for all). Patients with apical variant had lower levels of global iVP compared to patients with predominant septal LVH and diffuse concentric LVH (Fig. A, right).

Conclusions:
Myocardial stiffness measured noninvasively by the intrinsic wave method is highly abnormal in HCM. This novel approach allows mapping of myocardial elasticity of the entire left ventricle and shows promise to become a clinical tool for evaluation of patients with diastolic tissue abnormalities.
Abstract 11903: Assessment of Left Ventricular Relaxation Time by Pulse Wave Analysis: Association With Arterial Compliance
Authors: Melnikov Vladimir N
Published: April 2024

Introduction:
The long left ventricular relaxation (LVR) has been shown as a marker of diastolic dysfunction. This parameter is usually measured by such complex methods as echocardiography and radionuclide technique. This study tests a possibility to evaluate LVR time by applanation tonometry and explores its association with arterial distensibility basing on the assumption of a parallelism in contractile mechanics between striated cardiac muscle and arterial smooth muscle.

Methods:
Overall, 352 normotensive subjects (age 18-76 yrs.) were enrolled in this study. The LVRT was assessed by pulse wave analysis (SphygmoCor) and measured as difference between the end of systole (ejection duration point, ED, corresponding to the closure of aortic valve) and the time of peak pressure (T1, figure) generated by systolic antegrade wave in aortic root (LVRT,%=(ED-T1)/Tf*100). Intima-media thickness of brachiocephalic arteries and heart dimensional indices were measured by ultrasonography.

Results:
A difference was established in LVRT between age-matched female (47.9 yr., 24.8±2.8 %, M±SD, n=158) and male groups (47.1 yr., 21.7±2.9 %, n=192, p<0.001, T-test). In men, LVRT was associated with age (r=0.33), end systolic volume (partial r=0.39; age and HR= const.), augmentation index (AIx@75, r=0.33), aorta-to-radial pulse pressure amplification (r=-0.24), and time to reflection wave (r=-0.25, two-sided p<=0.001 for all cases). The association of LVRT with AIx remains significant after adjusting for age, Tf, and SBP in multiple regression analysis (GLM module, SPSS). In women, less pronounced associations were found. No relations were seen of LVRT with intima-media thickness of brachiocephalic arteries and carotid-radial pulse wave velocity in both sex groups.

Conclusions:
In healthy subjects, the long LVR assessed by PWA was associated with stiff conduit arteries of upper limbs.

Figure
. Pulse pressure profile in the aortic root as a result of pulse wave analysis
Abstract 11912: Risk Stratification of Life Threatening Ventricular Tachyarrhythmias in Patients With Non-Ischemic Cardiomyopathy
Authors: Goldenberg Ido , Kutyifa Valentina , Zareba Wojciech , Younis Arwa , Goldenberg Ilan , Aktas Mehmet
Published: April 2024

Background:
The implantable cardioverter defibrillator is effective in reducing mortality among patients with heart failure (HF) due to ischemic heart disease. More recent clinical trial data have called into question the benefit of an ICD in patients with HF due to non-ischemic cardiomyopathy (NICM).

Objective:
The purpose of this study was to identify a risk stratification score among patients with NICM receiving a primary prevention ICD.

Methods:
The study population comprised 1842 patients with NICM who were enrolled in the MADIT and RAID trials. We used Fine and Gray analysis to develop a model for the occurrence of ventricular tachycardia/fibrillation (VT/VF), while accounting for the competing risk of death. Patients were grouped into 3 strata based on their risk score.

Results:
Five factors associated with increased risk of VT/VF were identified: ICD vs cardiac resynchronization therapy with a defibrillator (CRT-D), prior history of non-sustained VT, male gender, ejection fraction ≤ 25%, and Black Race. A score was generated based on this model and the patients were stratified into three risk groups. The four-year cumulative incidences of VT/VF in the low-, intermediate-, and high-risk groups were 19%, 37%, 52%, respectively (p<0.001 for the overall difference; Figure). Internal validation using a bootstrapping yielded a median c-statistic of 0.69 (95% CI 0.66-0.74).

Conclusions:
Our findings suggest that patients with NICM can be risk stratified for VT/VF using a combination of clinical and echocardiographic findings.
Abstract 11925: Comparison of Right Ventricular Outflow Tract-Dominant Hypertrophic Type With Diffuse Type Using Cardiac CT for J Waves and Clinical Parameters in Pulmonary Hypertensive Patients
Authors: Funabashi Nobusada , Ozawa Koya , Nakamura Kohki , sasaki takehio , Naito Shigeto , Kobayashi Yoshio
Published: April 2024

Introduction:
J waves are specific in patients with hypothermia, idiopathic ventricular fibrillation, or brain damage. Patients with pulmonary hypertension (PH) may show right ventricular (RV) hypertrophy and fibrosis, leading to abnormal ECG findings. On cardiac CT of PH, two RV hypertrophic (RVH) types are seen, namely RV outflow tract dominant and RV diffuse.

Hypothesis:
We hypothesize that these two morphological RVH types might have different effects on ECG findings including J waves, and clinical severity in PH patients.

Method:
We retrospectively analyzed 43 PH patients (33 females, 55±15 yrs, 31 chronic thromboembolic PH, 7 idiopathic pulmonary arterial (PA) hypertension). Cases were divided into 3 groups: RV outflow tract dominant RVH (gp 1) (N=6), RVH diffuse (gp 2) (N=26), and no RVH (gp 3) (N=11).

Results:
In gp 1, one (17%) had J waves in II, III, and aVF leads with a maximum RV wall thickness on end-diastole 7.5mm. In gp 2, three (12%) had J waves in II, III, and aVF leads with maximum RV wall thickness on end-diastole 6.7, 6.1, and 5.6mm, respectively. In gp 3, none (0%) had J waves. In gp 1, all six (100%) had a negative T wave in V1-3 leads or beyond and in gp 2, 24 (92%) had a negative T wave in V1-3 leads or beyond (P=0.483). There were significant positive correlations between maximum RV wall thickness in end-diastole and plasma brain natriuretic peptide (BNP) in gp 1 (R=0.44) but no correlations in gp 2. There were significant positive correlations between maximum RV wall thickness in end-diastole and estimated PA systolic pressure (PASP) on TTE in gp 1 (R=0.38) but no correlations in gp 2.

Conclusions:
In 32 PH participants with an organized RV myocardial change, such as RV outflow tract dominant and diffuse type RVH, 17% and 12% had J waves in II, III, and aVF leads and most of them had a negative T wave in V1-3 leads or beyond. Only RV outflow tract dominant RVH showed significant positive correlations between maximum RV wall thickness in end-diastole, plasma BNP and estimated PASP.
Abstract 11932: Outcome Predictions Using Machine Learning in Atrial Fibrillation-Related Stroke
Authors: Jung Jin-Man , Jeon Eun-Tae
Published: April 2024

Introduction:
Atrial fibrillation (AF) is one of the most important risk factor for poor clinical outcomes in stroke patients, however, until now, there has been no outcome prediction model in stroke concomitant with AF. The aim of study was to build a powerful machine learning model for predicting outcomes in AF-related stroke.

Methods:
Using a multi-center prospective stroke registry from 11 tertiary centers in South Korea performed between January 2013 and December 2015, a total of 3090 patients were included. Various clinical, laboratory and imaging factors and medications at discharge were collected. Outcomes included recurrent stroke, all-cause death, major adverse cardiovascular events (MACE), major hemorrhage, and any gastrointestinal hemorrhage. Random survival forest and eXtreme Gradient Boosting (XGBoost) were used for machine learning and Cox proportional hazard method as a baseline model and five stroke prediction scoring systems including CHADS
2
, CHA
2
DS
2
-VASc, ATRIA, ESRS (Essen Stroke Risk Score), and FSS (Fukuoka stroke scale) were selected. Among the data, 25% was randomly held out and used only in model performance evaluation. The remaining 75% data was used in model construction with 10-fold cross validation scheme. To compare performance between models, prediction power and error were evaluated as concordance index and integrated brier score, respectively.

Results:
The highest concordance index was achieved with XGBoost for all-cause death (0.899, 95% CI, 0.893 -0.905) and MACE (0.843, 95% CI, 0.838 - 0.848) and with random survival forest for predicting major hemorrhage (0.789, 95% CI, 0.729 - 0.838) and any gastrointestinal hemorrhage (0.819, 95% CI, 0.767 - 0.861). For predicting recurrent stroke, all models showed very poor performances and Fukuoka stroke scale achieved the highest concordance index (0.580, 95% CI, 0.561 - 0.598). Machine learning models achieved the lowest prediction error in all outcome predictions among models.

Conclusions:
Machine learning model can be useful for predicting outcomes in AF-related stroke. However, the performance of all models was relatively low with regards to recurrent stroke. Further study is needed to validate this machine learning approach.
Abstract 11946: Comparison of Unsupervised Learning Approaches Applied to Electronic Health Record Traits in Heart Failure
Authors: Reza Nosheen , Bone William P , Singhal Pankhuri , Yang Yifan , Verma Anurag , Murthy Ashwin C , Denduluri Srinivas , Adusumalli Srinath , Ritchie Marylyn , Cappola Thomas P
Published: April 2024

Introduction:
Unsupervised machine learning (UML) applied to high dimensional data has been used to discover cardiovascular disease subtypes; however, the reproducibility of subtypes identified by different algorithms has not been explored. We compared the ability of several promising UML and clustering algorithms to identify heart failure (HF) subtypes using high dimensional electronic health record (EHR) data.

Methods:
Using the Penn Medicine EHR, we identified all patients who had
>
2 instances of ICD-10-CM HF diagnosis. We extracted 1272 EHR-based features (vital signs, demographics, echocardiographic measurements, laboratories, comorbidities) from time of HF diagnosis and limited the cohort based on data completeness (n=8569). We selected the following methods based on prior success in simulation studies and used them to identify HF subtypes: Similarity Network Fusion (SNF), Locally Linear Embedding (LLE), Modified LLE, Uniform Manifold Approximation and Projection (UMAP), and Principal Component Analysis (PCA) followed by several clustering algorithms including K-means, Density-based spatial clustering of applications with noise (DBSCAN), and Spectral Clustering. K groups 2-12 were evaluated. Clustering performance was assessed by silhouette score and visual separation.

Results:
Model visualizations are shown in the Figure. Highest silhouette score achieved for each model varied widely from 0.02-0.62; optimal cluster number ranged from 2-4 across models. Normalization and standardization of continuous data did not significantly alter silhouette scores or optimal cluster number.

Conclusions:
HF subtypes identified through UML applied to EHR data may vary substantially depending on the algorithms used. Benchmarking strategies to evaluate reproducibility of UML in the EHR are needed to ensure valid HF patient stratification and phenotypic refinement.
Abstract 11949: Disease-Specific and Comorbidity-Related Polygenic Risk in Spontaneous Coronary Artery Dissection
Authors: Tarr Ingrid , Hesselson Stephanie , Iismaa Siiri , Troup Michael , Young Paul , Mishra Ketan , Wong Claire , Junday Keerat , Humphreys David , Dunwoodie Sally , Fatkin Diane , Muller David , Graham Robert M , Giannoulatou Eleni
Published: April 2024

Introduction:
Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute coronary syndrome that typically affects younger women (24-52 years). Several comorbidities have now been reported, including migraine, fibromuscular dysplasia (FMD), connective tissue disorders, anxiety, and depression. Associations between SCAD and other conditions, such as autoimmune disorders, have been reported but remain contentious. SCAD is known to have a genetic element: both common and rare variants have been associated with the disease and familial clustering has been identified. However, the genetic etiology is not well resolved although common variants have been identified between SCAD, FMD, and migraine.

Aims:
We sought to determine if there is a polygenic disease burden of common genetic variation in a cohort of sporadic SCAD cases, and shared genetics between SCAD and reported comorbidities via the application of polygenic risk scores (PRSs) for these comorbidities.

Methods:
A cohort of 173 sporadic European SCAD cases and 1314 European controls were genotyped (88 cases, 1127 healthy elderly controls and 76 non-SCAD cardiomyopathy-diseased patients by whole genome sequencing; 85 cases and 111 controls by Axiom UK Biobank and PMDA array, respectively). Differences in genetic risk was assessed for cases and controls using established PRS, specific to either SCAD or conditions reported to be comorbid.

Results:
SCAD cases showed significantly higher SCAD-PRS than did controls (WGS p = 1.372e-09; array p = 5.264e-05). In contrast, there were no differences in SCAD-PRS between non-SCAD patients and controls (WGS only: p-value = 0.291) and non-SCAD patients also had lower risk than SCAD cases (WGS only: p-value = 2.08e-07). Multiple PRS derived from comorbid disorders are currently being investigated in this cohort.

Conclusions:
We have shown that there is a common genetic risk element to SCAD, while genetic risk for, and, therefore, genetic overlap with, reported comorbidities in SCAD will be further discussed. These findings illustrate the role of common variants in SCAD etiology and may further contribute to our understanding of the mechanisms leading to SCAD formation.
Abstract 11953: Hemorrhagic Insults And Secondary Takotsubo Syndrome: A New In-vitro Model
Authors: Forster Carola Y , Thal Serge C
Published: April 2024

Introduction:
Hemorrhagic insults result in very devastating forms of cerebral damage. The effects on the blood-brain barrier are so far examined only ex vivo and show reduced integrity.

Hypothesis:
There is a connection between hemorrhagic bleeding and secondary takotsubo syndrome (TTS), leading to a poor outcome in comorbidity. Our hypothesis is that through the elevated catecholamine levels and proinflammatory cytokine leves demonstrated to be present in the serum of TTS patients, BBB integrity will be impaired by TTS blood exposure more pronounced and/or early than by control group blood exposure (potentially fueling cardiac arrhythmia/ TTS at the brain-heat axis).

Methods:
Our study aims to establish an in-vitro cell culture model of blood exposure from heathy and TTS patients and measure the time-dependent effect on integriy of brain capillary cell monolayers as a basis to further examine the connection between hemorrhagic insults and TTS. We perfomed blood and serum exposure from healthy and TTS subjects to murine brain microvascular endothelial cells (cerebEND) derived from the cerebellum as an established model of the blood brain barrier and evaluated effects on barrier components by PCR and western blot.

Results:
Decreased monolayer integrity was readily detectable, reduced levels of Claudin-5 and Occludin were confirmed by RT-qPCR and Westernblot. Both tight-junction proteins show a time-dependent reduction.

Conclusions:
the development of the model seems successful, as ex-vivo studies previously showed matching results. Exposure of monolayer to TTS patient blood clearly showed a faster and more pronounced disintegration of brain endothelial monolayer.