bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 11954: Coronary Atherosclerotic and Inflammatory Changes for Varying Lengths of Myocardial Bridge
Authors: Watanabe Tasuku , Nishimiya Kensuke , Ota Hideaki , Higuchi Satoshi , Yamamoto Erika , Takeuchi Satoshi , Fukui Kento , Suda Akira , Godo Shigeo , Shindo Tomohiko , Hao Kiyotaka , Kikuchi Yoku , Takahashi Jun , Yasuda Satoshi
Published: April 2024

Background:
Myocardial bridge (MB) is a frequent cause of ischemia and nonobstructive coronary artery disease (INOCA). Coronary segments proximal to the MB likely develop atherosclerotic lesions due to altered endothelial shear stress (ESS) as a consequence of systolic compression beneath MB. We recently demonstrated that optical coherence tomography (OCT)-delineated adventitial vasa vasorum (AVV) formation as a marker for vascular inflammation are extensive at the segments proximal to the MB. This study was aimed to examine coronary atherosclerotic and inflammatory changes depending on varying MB length.

Methods and Results:
Amongst 165 INOCA patients who underwent both coronary computed tomography angiography (CCTA) and co-registered OCT, 31 subjects with CCTA-derived MB in the left anterior descending coronary arteries were enrolled (
Fig. A
). Biplane coronary angiography was merged with serial OCT cross-sections to be three-dimensionally volume-rendered for the ESS mapping (
Fig. B
). Using OCT, tissue type of each coronary segment was classified as intimal hyperplasia (IT), fibrous plaque (FP), fibroatheroma (FA), or fibrocalcific plaque (FC). The segment proximal to the MB was with the lowest ESS level, where OCT displayed the lesion with FA (
Fig. B
). Indeed, advanced lesions with FA and FC were more frequently noted at the sites 5-mm proximal to the MB when compared to the middle portions beneath MB (
Fig. C
). Notably, % intimal plus medial (I+M) area = [(I+M area/vessel area) х100] as a marker for atherosclerotic changes were correlated with the lengths of MB at the proximal segments (
Fig. D
). Lesions with FP, FA and FC showed longer MB lengths as compared with IT (One-way ANOVA. P<0.05). Likewise, AVV formation was positively correlated with the length of MB (
Fig. E
).

Conclusion:
These results indicated that in addition to the ESS, varying MB lengths alter atherosclerotic and inflammatory coronary lesions proximal to the MB.
Abstract 11963: A Digital Heart Failure Coach Intervention for Improving Education, Self-Management and Outcomes in Patients Admitted for Acute Decompensated Heart Failure: Barriers to Effective Implementation
Authors: Zisis Georgios , Carrington Melinda J , Oldenburg Brian , Whitmore Kristyn , Lay Maria , Huynh Quan , Neil Christopher , Ball Jocasta , Marwick Thomas
Published: April 2024

Introduction:
Heart Failure (HF) education is fundamental for improving outcomes. The use of mobile health (m-health) devices and Artificial Intelligence (AI) are becoming more broadly available. We designed an avatar style digital HF coach (HF-app) to improve HF knowledge and self-care management.

Hypothesis:
We hypothesized that an avatar style HF-app could improve outcomes by enhancing HF knowledge and improving quality of life and self-care behaviors in patients admitted for Acute Decompensated HF (ADHF).

Methods:
The Risk-HF trial recruited patients admitted for ADHF who were at high risk for hospital readmission and/or death (defined by a previously developed risk score, ETHELRED trial). Patients were randomized to usual care or intervention, in which the HF-app was a component of a multifactorial intervention aimed at reducing HF readmissions. Our HF-app was designed to engage daily with the patient by monitoring HF symptoms and delivering education over 52-days.

Results:
Over a period of 16 months (August 2019 up until December 2020), 36 of 74 high risk patients were randomized to the intervention arm and were offered education with our HF-app. Of these, 26/36 (72%) had restricted access to the HF-app (
unable to use a tablet device and/or unwilling to be taught how to use it, n=20; no internet access, n=4; died in hospital n= 2
) and 10/36 (28%) were enrolled to use the HF-app [

gender male n=7; median age 71.5 years,
p<0.01
(IQR: 57.50 - 78.50); mean years of education 11.6(±2.5),
p<0.01

]. Younger patients [

Odds Ratio (OR) 0.89 [95% Confidence Interval (CI): 0.82-0.97],
p<0.01

] and those with a higher education level [

OR 1.58 (1.09-2.28),
p=0.03

] were more likely to enroll. Of those enrolled, only two patients engaged and completed ≥70% of the program. Six of the remaining 8 patients who did not engage were readmitted.

Conclusions:
Our study provides a note of caution in studies using m-health devices and apps in critically ill and elderly patients with unstable HF. Future research should consider how to use such technology-based interventions with elderly patients as well as to target younger ADHF patients, which may provide stronger evidence of benefits in patient self-care and outcomes.
Abstract 11965: Association of Ticagrelor versus Clopidogrel With Bleeding, Dyspnea, and Premature Discontinuation in Patients With Acute Coronary Syndrome
Authors: Kang Min , Kim Kyehwan , Ahn Jong-Hwa , Park Hyun Woong , Koh Jin-Sin , Park Yongwhi , Hwang Seok-Jae , Hwang Jin-Yong , Jeong Young-hoon
Published: April 2024

Introduction:
Current clinical data have raised the issues regarding the risk of adverse events (e.g. bleeding and dyspnea) and the limited clinical benefit during ticagrelor vs. clopidogrel treatment in patients with acute coronary syndrome (ACS).

Hypothesis:
Association between bleeding and dyspnea during dual antiplatelet therapy (DAPT), and it would be related with drug switch or discontinuation.

Methods:
East Asian patients presented with ACS were undergoing percutaneous coronary intervention, and were treated with DPAT with ticagrelor (n=270) or clopidogrel (n=674). At 30-day follow-up, we evaluated platelet function with VerifyNow, and incidence of bleeding (BARC criteria) and dyspnea (MMRC scale) using the dedicated questionnaire.

Results:
During 30-day follow-up, ACS patients on ticagrelor showed the higher rates of bleeding (45.6% vs. 23.6%; HR, 2.71) and dyspnea (26.3% vs. 13.6%; HR, 2.25) compared with those on clopidogrel. In terms of low platelet reactivity (LPR), ticagrelor showed the lower cutoff (‘PRU≤20’) compared with clopidogrel (‘PRU≤110’). In multivariate analysis, LPR phenotype (OR, 2.70), not type of P2Y
12
inhibitor (OR, 1.34), was significantly associated with the risk of bleeding
(Figure)
. In addition, type of P2Y
12
inhibitor (OR, 2.14) and bleeding episode (OR, 2.83) increased the risk of dyspnea
(Figure)
. At 12-month follow-up, ticagrelor treatment showed a higher risk of drug discontinuation than clopidogrel treatment (27.8% vs. 4.7%; HR, 7.71). During ticagrelor administration, patients with both dyspnea and bleeding had a higher rate of drug discontinuation compared to those without both dyspnea and bleeding (adjusted HR, 3.05).

Conclusions:
This study suggests that incidence of bleeding and dyspnea was frequent during ticagrelor treatment in East Asian patients with ACS. A close association between bleeding and dyspnea increased the risk of drug discontinuation during ticagrelor treatment.
Abstract 11970: Left Atrial Hemodynamics and Invasive Functional Testing to Characterize Heart Failure With Preserved Ejection Fraction in Patients With Atrial Fibrillation
Authors: Ariyaratnam Jonathan P , Mishima Ricardo , Gallagher Celine , Emami Mehrdad , Wong Christopher , MALIK VARUN , Fitzgerald John , MacNamee Olivia , Lau Dennis H , Elliott Adrian , Sanders Prashanthan
Published: April 2024

Introduction:
Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) commonly coexist. The contribution of abnormal left atrial (LA) hemodynamics to the development of HFpEF in symptomatic AF patients is unknown.

Hypothesis:
Hemodynamic testing of patients with symptomatic AF will reveal coexistent HFpEF associated with increased LA pressures and stiffness.

Methods:
Consecutive patients with AF and preserved ejection fraction (awaiting AF ablation) were prospectively recruited. Participants underwent exercise echocardiography and cardiopulmonary exercise testing (CPET), and were grouped according to low, intermediate or high probability of HFpEF based on the ‘HFA-PEFF’ score. At ablation, participants underwent invasive monitoring of LA and right atrial pressures during infusion of 15mL/kg of normal saline directly into the LA over 8 minutes. LA size was monitored during infusion with transesophageal echocardiography. LA stiffness was calculated as Δ LA pressure/Δ LA diameter. Statistical comparison across groups was performed using analysis of variance.

Results:
Amongst 64 participants, probability of HFpEF was low in nine (14%), intermediate in 39 (61%) and high in 16 (25%) participants. High probability HFpEF was associated with higher baseline mean LA pressure (Fig. 1A) and greater increases in peak (p=0.06) and nadir LA (p<0.01) pressures with saline loading, without significant increases in RA pressure. LA stiffness was increased in patients with high probability of HFpEF (Fig. 1B). Non-invasive testing revealed reduced peak VO
2
(p=0.01), reduced LA emptying fraction at rest and with exercise (p<0.01) and reduced LA reservoir strain (p<0.01) in participants with higher probability for HFpEF.

Conclusions:
In AF patients undergoing ablation, 25% meet the criteria for HFpEF. Higher probability of HFpEF is characterized by increased LA pressures and LA stiffness, exercise intolerance and reduced LA function.
Abstract 11971: Predicting Significant Cardiomyopathy in Coronary Artery Disease Through Application of Predictive Machine Learning (ML) Algorithms
Authors: English Carter W , Vijayaraghavan Sairamvinay , Flack Jeffrey , Mohapatra Prasant , Srivatsa Uma N
Published: April 2024

Introduction:
Left ventricular ejection fraction (LVEF) of ≤ 40% in patients with coronary artery disease (CAD) is associated with an increased risk of sudden cardiac death. Accurately predicting LVEF at clinical follow-up can identify patients needing an implantable cardioverter-defibrillator device.

Hypothesis:
To develop a predictive algorithm using ML methods for predicting LVEF on follow-up echocardiogram for individuals with CAD.

Methods:
We identified the 10 most significant predictors of follow-up LVEF using a variety of feature selection algorithms from 109 variables based on clinical, demographic, ECG, and echocardiography data from 2116 hospitalized patients diagnosed with CAD. Various predictive ML algorithms were constructed to predict follow-up LVEF at 60 to 730 days from admission through regression, binary classification (LVEF ≤ 40% and LVEF > 40%), and multi-classification analysis. AUC scores, accuracy, precision, F Score, and recall were calculated for each model to evaluate outcome performance.

Results:
N = 421 patients had LVEF ≤ 40% on presentation and 535 had LVEF ≤ 40% on follow-up. We observed that binary classification tasks outperformed regression and multi-classification tasks (Graph 1). In a binary classification setting, the top-performing models were simple neural networks, random forests, or logistic regression. (Table 1).

Discussion:
We developed various ML algorithms in multiple settings to optimize predicting follow-up LVEF with patients with CAD. With an enhanced ability to predict reduced LVEF, we aspire to improve the timing and efficiency of appropriate ICD implantation in patients based on current guidelines.
Abstract 11977: Cardiac Resynchronization Therapy and the Risk of Ventricular Tachyarrhythmia
Authors: Goldenberg Ido , Aktas Mehmet , Zareba Wojciech , Younis Arwa , Kutyifa Valentina
Published: April 2024

Introduction:
Cardiac Resynchronization Therapy (CRT) was shown to be associated with clinically significant benefit by lowering mortality, heart failure hospitalizations, and improving quality of life in patients with reduced left ventricular function and a wide QRS. However, there are conflicting data on the effect of CRT on the risk of ventricular tachycardia or ventricular fibrillation (VT/VF) in implantable cardioverter defibrillator (ICD) recipients.

Methods:
The study population comprised 4531 patients enrolled in the 5 landmark ICD trials (MADIT-II, MADIT-CRT, MADIT-RIT, MADIT-RISK, and RAID) implanted with an ICD. Three patient groups were generated: ICD with a narrow QRS complex (n=2208), ICD alone with a wide QRS (n=1105), and patients with both ICD and a CRT (CRT-D) (n=2198). We compared the cumulative incidence of VT/VF in each group while accounting for the competing risk of non-arrhythmic mortality using the Fine and Gray Method.

Results:
Recipients of a CRT-D were more likely to be female, to use a beta blocker, and have a higher New York Heart Association Functional Class. The cumulative incidence of VT/VF at 4 years of follow-up in patients with a CRT-D was significantly lower (24%) as compared with patients with an ICD with or without a wide QRS (31% for both; p<0.001 for the overall difference). Findings were consistent for the endpoints of appropriate ICD shocks and fast VT/VF (>200 bpm). Multivariate analysis showed that compared to ICD-only therapy (with wide QRS), treatment with CRT-D was associated with a significant 20% (p=0.006), in the endpoint of VT/VF and 36% reduction in the endpoint of appropriate shock for VT/VF (p<0.001).

Conclusion:
Our data from 5 landmark clinical trials suggest that cardiac resynchronization therapy exerts important antiarrhythmic properties, leading to a significant reduction in the risk of ventricular tachyarrhythmia and appropriate ICD shocks in patients implanted with an ICD for primary prevention.
Abstract 11979: Activation of Growth Hormone Releasing Hormone Receptor Signaling as Potential Therapeutic Approach to Treat Heart Failure With Preserved Ejection Fraction
Authors: Kanashiro-takeuchi Rosemeire M , Takeuchi Lauro , Balkan Wayne , Cai Renzhi , Schally Andrew , Hare Joshua M
Published: April 2024

Introduction:
Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of the HF cases and is steadily rising. To date, there no effective therapies for HFpEF. Growth hormone-releasing hormone (GHRH) has shown a broad range of regulatory influences in the cardiovascular system, aging and obesity in preclinical and clinical studies; therefore, we hypothesize that GHRH-agonists (GHRH-A) can attenuate/reverse the HFpEF phenotype.

Methods:
C57BL6N mice received a high fat diet (HFD) plus L-NAME for 5 weeks (HFD+L-NAME) to induce HFpEF. Cardiac morphology and function was then assessed by echocardiography, and animals were randomized to receive daily injections of GHRH-A (200 μg/Kg) or placebo (vehicle). Control animals received neither HFD+L-NAME nor treatment. Mice were acclimated to treadmill exercise testing and for systolic blood pressure (SBP) measurements.

Results:
Baseline characteristics following 5 weeks of HFD+L-NAME showed no difference in ejection fraction (EF), but isovolumetric relaxation time (IVRT) and E/A ratio were increased, while E/E’ ratio decreased compared to control (Fig1A-D, *p<0.05, ****p<0.0001 t-test). Running distance (Fig1E) after 1-week of GHRH-A treatment suggests improvement over placebo-treated mice. Similarly, SBP (Fig1F) appears to be returning to normal after 10 days (**p<0.01, Kruskal-Wallis test).

Conclusions:
Our results corroborate exercise intolerance and hypertension in the HFD+L-NAME placebo and suggest that even short-term GHRH-A treatment produces beneficial effects on exercise tolerance and SBP. Thus, GHRH-A therapy may be a potential therapeutic strategy for treatment of cardiometabolic HFpEF phenotype.
Abstract 11980: Patients With Esophageal Cancer Show Reduction in Myocardial Function and Reduced Oxygen Consumption During Exercise After Chemo-Radiotherapy
Authors: Soendergaard Mette Marie Astrup M , Nordsmark Marianne , Nielsen Kirsten Melgaard M , Poulsen Steen H
Published: April 2024

Introduction:
Chemo-radiotherapy (CRT) may induce myocardial dysfunction, congestive heart failure and impaired physical performance in patients with esophageal cancer (EC). We aimed to investigate left ventricular function at rest and at peak exercise using echocardiography (ECHO) before and after completed CRT.

Material and Methods:
We enrolled 47 EC patients, referred to curative CRT, (41.4-50 Gy in 23-28 fractions and carboplatin, paclitaxel) followed by surgery (nCRT), n=38 or CRT, n=9. Evaluation included myocardial function, physical performance, cardiac biomarkers, electrocardiogram, ECHO at rest and during stress, and by cardiopulmonary exercise test before and post CRT. The primary endpoint was changes in LV global longitudinal strain (GLS). Secondary endpoints were LVEF, LV diastolic function, LVEF and GLS at peak exercise and maximal oxygen consumption.

Results:
Median age was 67 years, 94% males. The median time to post CRT follow-up was 1 day (IQR 0,6). There was a significant drop in LVEF and GLS at rest 56.7 % vs. 53.8% and 17.6 % vs. 16.4%, respectively (p=0.03; p=0.004). Ten patients had an absolute fall of at least 5% in LVEF and 2.5% in GLS. Signs of LV diastolic dysfunction increased from 13% to 21%, p=ns. Peak VO2 and maximal work capacity significantly decreased 21.2 vs. 18.8 and 5.9 vs. 5.4 respectively (p =0.000 and p=0.000). We found a weak correlation between change in GLS at peak exercise and fall in VO2 max (r=0.369 p=0.018).

Conclusion:
Left ventricular function and physical performance decreased in patients with EC after completed CRT. The decrease of peak V02 performance was only weakly significant related to the changes of peak LV function which indicates that other factors are involved in the decline of the physical performance after CRT.
Keywords
Esophageal cancer, chemoradiotherapy, cardiac function, working capacity, cardiotoxicity.
Abstract 11983: Prolonged Coronary Arterial Phase and Recurrent Ischemia Are Hallmarks of Repeat Heart Failure and Sudden Cardiac Death in Patient With Dilated Cardiomyopathy and Patent Coronary Arteries an Angiographic and Machine Learning Analysis
Authors: Nguyen Thach N , Huynh Thanh N , Le Thoa , Le Minh Anh , Nguyen Thu Q , Le Chuong T , Nguyen Nguyet , Vu Loc , Le Minh H , Ho Dung T , Rigatelli Gianluca , Talarico Ernest , Zuin Marco , Pham Hung N , Cao Thinh , Nguyen Thuong Nghia T
Published: April 2024

Introduction:
Many patients with dilated cardiomyopathy (DilCM) and patent coronary arteries came to emergency room with shortness of breath, chest discomfort, elevated troponin level. Many similar DilCM patients did not. Why?

Hypothesis:
In DilCM and patent coronary arteries, could the combination of coronary slow flow and ischemia is a predictor of recurrent heart failure (HF) and sudden cardiac death (SCD)?

Methods:
Patients with DilCM underwent coronary angiography and were enrolled if the coronary arteries were patent. In a new dynamic angiographic technique, contrast was injected until the index coronary artery was completely opacified. Then the manual injection stopped. At this moment, the blood in “white” color moved in, displacing the black contrast. The shape and movement of the blood flow could be clearly analyzed above a background of black contrast. The first study measurement was the arterial phase (AP) which was calculated by visual angiographic assessment and artificial intelligence program (Machine Learning algorithms). The AP was defined as the duration from the entry of blood until all the contrast was cleared from the distal index artery. The second study factor was the series of troponin levels. The patients were followed up for (1) recurrent HF hospitalization, (2) aborted ventricular tachycardia by defibrillator (ICD) and (3) SCD.

Results:
40 patients with DilCM were enrolled (ejection fraction (EF) averaged 34%) and followed up for 3 years. In 35 DilCM patients, the AP phase was extremely prolonged at 120 frames or 8 seconds compared with 1.56 seconds of historical controls. The results showed:
Group A
(5 patients): No prolonged AP, no Ischemia: so no HF admission, no death if on guideline-directed medical therapy (GDMT), 3 patients had EF recovered >50%.
Group B
(25 patients): Prolonged AP and No ischemia: rare hospitalization, ICD shock, no death if compliant with GDMT.
Group C
(10 patients) Prolonged AP and ischemia: recurrent HF, ICD shocks and 6 SCD

Conclusions:
In patients with DilCM, prolonged AP and recurrent ischemia were the markers of recurrent HF and SCD. The patients with only prolonged AP were at medium risk and stable if on GDMT. Patients with normal AP without ischemia were at low risk and the EF could recover to normal with GDMT.
Abstract 11994: Proteomic Evaluation And Biomarker Identification In Tricuspid Regurgitation
Authors: Yu Si-Yeung , Tse Yi Kei Stephanie , Li Hang Long , Ren Qingwen , Wu Meizhen , LI Kwan Yu , Wong Pui Fai , Lam Lok Yee Jane , Yu Shuk Yin , Yiu Kai Hang
Published: April 2024

Introduction:
Not only are mechanisms involved in tricuspid regurgitation (TR) incompletely understood, there is no established means of risk stratification for patients undergoing tricuspid valve interventions. A better understanding of underlying biological mechanisms allows for identification of therapeutic targets as well as biomarkers for disease staging, monitoring, and prediction following intervention.

Methods:
Preoperatively, 276 patients undergoing tricuspid annuloplasty, divided into training and validation cohorts, were assessed and followed-up for adverse events defined as death or heart failure requiring hospitalisation. Preoperative plasma samples were analysed for levels of cardiac troponin-T, NTproBNP, as well as 91 other markers (Olink multiplex assay). Correlated network analysis was used for clustering plasma markers. The relations of clusters to echocardiographic parameters and adverse outcomes were assessed by linear and Cox regression respectively. Pathway overrepresentation analysis was conducted to ascertain biological mechanisms overrepresented in relevant clusters by enrichment with reference to existing knowledge.

Results:
Over a median follow-up period of 3.7 years, 83 adverse events occurred. Two clusters of biomarkers in the training cohort significantly correlate with right chamber and tricuspid annular dilatation, regurgitant jet area, effective regurgitant orifice area and/or adverse outcomes following tricuspid annuloplasty (P<0.05). The two clusters are represented by hub proteins TNF Receptor Superfamily Member 10A and TRAIL receptor 2. Overrepresented biological pathways in the two clusters include immunological responses, cytokine production regulation, and responses to lipids. Both clusters are conserved in the validation cohort.

Conclusion:
Immunoinflammatory pathways may be implicated in tricuspid regurgitation, and markers related to such pathways show prognostic significance.
Abstract 11998: The microRNA-378 and Estrogen-Related Receptor Gamma Axis Regulates Metabolic Inflammation and Lipoprotein Metabolism: A Potential Therapeutic Target for Atherosclerosis
Authors: Su Qiaozhu , Kaluzny Szczepan
Published: April 2024

MicroRNAs (miRNAs) are non-coding small RNAs that interact with their targeted mRNAs, resulting in decay or translational repression of the targeted mRNAs. The estrogen-related receptor (ERR)γ is an orphan nuclear hormone receptor. MiRNAs and ERRγ play pivotal roles in the pathophysiological conditions of metabolic diseases.

The objective of this study is to determine the impact of miR-378a and its targeted gene ERRγ in metabolic inflammation and HDL metabolism, and explore the therapeutic potential of antigomic miRNA in atherosclerosis. Bioinformatics analysis of hepatic miRNA sequencing profile from mice fed a lipogenic diet (high-fructose) revealed that miR-378a was upregulated and served as a hub in a regulatory network that collaboratively targets multiple metabolic signal molecules in energy metabolism, mitochondrial fatty acid β-oxidation (FAO), and lipoprotein metabolism. Specifically, the upregulated miR-378a induced by fructose suppressed expression of ERRγ and genes involved in FAO (e.g., PPARα, CPT1α and ACOX1). In contrast, genetic depletion of miR-378a (miR-378aKO) significantly enhanced ERRγ expression, ameliorated mitochondrial oxidative stress and metabolic inflammation. Furthermore, miR-378aKO markedly stimulated expression of genes involved in HDL metabolism, including LXRα, ABCA1 and aopA4, leading to the increase of HDL-cholesterol and decrease of LDL-cholesterol in blood circulation. An
in vivo
VLDL secretion assay further revealed that miR-378aKO inhibited biogenesis and secretion of VLDL from the KO mouse liver, suggesting an improvement of atherogenic status in the absence of miR-378a. More importantly, treated the fructose-fed mice with nanoparticles carrying antagomir against miR-378a successfully reduced hepatic miR-378a expression, which was associated with significant restoration of ERRγ signaling and the associated mitochondrial FAO and HDL metabolism, indicated by the increased gene expression of PPARα, CPT1α and ACOX-1 as well as LXRα and apoA4, in the treated mice.

Conclusion:
These data indicate that manipulating miR-378a level can restore ERRγ signaling, improve FAO and lipoprotein metabolism. This novel finding may lend support to the therapeutic strategy of atherosclerosis.
Abstract 12337: Gender Specific Phenomapping and Outcomes in Ischemic Cardiomyopathy
Authors: Anthony Chris , Obuchowski Nancy , Popovic Zoran B , Tang Wai Hong W , Griffin Brian P , Flamm Scott D , Kwon Deborah H
Published: April 2024

Background:
There is limited data on gender specific remodeling and its associated risk in patients with ischemic cardiomyopathy (ICM). We conducted gender based phenomapping analysis using Cardiac MRI (CMR) variables to identify novel sex-specific phenotypes in patients with ICM. We then assessed if these phenotypes were predictive of overall survival.

Methods:
Patients with ICM
who underwent CMR between January 2002 and January 2017, were retrospectively evaluated
. Cluster analysis was performed using nearest centroid sorting with nine variables: left ventricular end systolic volume index (LVESVi), mitral regurgitation severity on CMR (MR) , left atrial volume index (LAVi), right ventricular ejection fraction (RVEF), RV end diastolic volume index (RVEDVi) , LVEF, LV mass index (LVmassi), left atrial ejection fraction (LAEF), and myocardial scar burden (Scar). For each cluster size a Cox proportional hazards model was used to test if the phenotypes were predictive of survival.

Results:
Data was analyzed from 407 males and 119 females. The optimal number of clusters was four, based on the ability of the phenotypes to predict overall survival. Phenotype was a statistically significant predictor of overall survival in men (p=0.002) and women (p=0.016) after adjusting for age, body mass index, renal function, hypertension, diabetes, revascularization and mitral valve intervention. (Figure 1a) These distinct phenotypes predicted survival differently in men compared to women. Of interest, there were significant differences in the contribution of each CMR variable to predict the phenotype based on sex. (Figure 1b) In females, CMR MR and RVEF were stronger contributors to the phenotype.

Conclusion:
Significant differences in phenotypic signatures based on gender are present in patients with ICM. These distinct phenotypes predicted survival differently in men compared to women and emphasizes the importance of sex specific risk stratification in the ICM cohort.
Abstract 12388: Impaired Mitochondrial Bioenergetics is Associated With Progression of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension
Authors: Zhang Peng , Vang Alexander , da Silva Goncalves Bos Denielli , Feord Julia , Mancini Thomas , Park Alexander , Choudhary Gaurav
Published: April 2024

Introduction:
Pulmonary arterial hypertension (PAH) has poor prognosis related to right ventricular (RV) dysfunction and failure. Yet, the underlying mechanisms of RV dysfunction remain unclear. Mitochondrial (mito) dysfunction and energy deficiency in RV have been implicated in RV dysfunction in PAH. A better understanding of RV mito function in PAH is critical in identifying novel therapies to improve RV function.

Hypothesis:
We hypothesized that impaired RV mito bioenergetics is associated with progression of RV dysfunction in PAH.

Methods:
PAH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats by injecting 20 mg/kg SU5416, followed by exposure to 3 wks of hypoxia (10% FiO
2
) and then 1-4 wks of normoxia. Control rats injected with vehicle were kept in normoxia. Echocardiography and hemodynamics were performed. RV tissues were collected for mito respiration assessments by high resolution O2K-FluoRespirometer (Oroboros), mito morphology assessments by electron microscopy, and biochemical assays.

Results:
PAH rats have increased RV systolic pressure, and RV systolic and diastolic dysfunction that ranged in severity from early PAH (1 wk SD), advanced PAH-mild to moderate RV dysfunction (7wks SD), to severe RV dysfunction (4 wks CDF - die of RV failure starting wk 5). Oroboros data show that mito complex I-coupled oxidative phosphorylation and maximal electron transfer capacity are significantly reduced in 7 wks SD rats (O
2
flux per mass: 216±21 vs. 90±19 and 209±22 vs. 91±22 pmol·s
-1
·mg
-1
, respectively, control vs. PAH,
P
<0.01, N=6 each), which are further reduced in 4 wks CDF rats. In parallel, RV ATP amount is significantly lower in PAH rats and is associated with increased apoptosis. There are no changes in mito membrane integrity by cytochrome c assays or in mito content by PCR. Mito size analysis show a significant increase in smaller mito in 4 wks CDF rats but not in 7 wks SD rats, suggesting increased mito fission in severe RV dysfunction.

Conclusions:
RV mito bioenergetics is impaired in PAH, progressively worsens with progression of RV dysfunction, and occurs prior to increased mito fission. Targeting bioenergetics may aid in developing new therapies to improve mito function and delay RV failure in PAH.
Abstract 12472: Development of an
in vitro
System to Study Mechanisms of Ultrasound-Targeted Microbubble Cavitation-Mediated Blood Brain Barrier Opening
Authors: Conway Grace E , Paranjape Anurag , Chen Xucai , Villanueva Flordeliza S
Published: April 2024

Introduction:
Ultrasound-targeted microbubble cavitation (
UTMC
) is being explored as a method to transiently open the blood brain barrier (
BBB
). While UTMC-mediated BBB opening is a promising avenue for increasing drug delivery to the central nervous system, its underlying mechanisms are incompletely understood. We sought to develop an
in vitro
system simulating cerebral endothelial barrier function, to facilitate studies aimed at exploring mechanisms of UTMC-mediated BBB opening.

Methods:
We developed a transwell model with murine brain microvasculature endothelial cells (bEnd.3) and rat C6 glioma cells on opposite sides of a support membrance. Three concentrations of lipid microbubbles (
MB
) were added before applying pulsed ultrasound (1 MHz, 10 μs pulse duration, 10 ms pulse interval) at 3 peak negative pressures (
PNP
) for 20 s. Endothelial barrier function was assessed using transendothelial electrical resistance (
TEER
) and permeability using 10 kDa Texas Red dextran. Cells were stained with Hoechst (nucleus), CellMask Deep Red (cell coverage), calcein-AM (viability), and propidium iodide (
PI
; sonoporation) Differences between experimental conditions were compared using unpaired 2-tailed t-test. Significance was defined as
p
<0.05.

Results:
At a given MB:cell ratio, higher PNPs increased the percent of viably sonoporated cells (
Fig 1A
), but caused increasing cell loss from the transwell (decrease in % area coverage) at PNP greater than 250kPa and MB:cell ratio higher than 3:1 (
Fig 1B
). Therefore, 250kPa ultrasound and 3:1 MB ratio were used in the permeability studies: BBB permeability increased by 15 min after UTMC as measured by TEER (
Fig 1C
) and dextran flux (
Fig 1D
), but recovered 1 hour later.

Conclusions:
We developed a co-culture transwell model of the BBB to simulate UTMC-induced reversible endothelial barrier hyperpermeability. This model will uniquely allow systematic investigation of mechanisms of UTMC-mediated BBB opening.
Abstract 12654: Direct Oral Anticoagulants (DOAC) versus Warfarin for the Treatment of Left Ventricular Thrombus (LVT) in Patients With or Without Cardiorenal Comorbidities, Including CKD (Chronic Kidney Disease) and Atrial Fibrillation: A Systematic Review and Meta-Analysis
Authors: Nso Nso , EMMANUEL KELECHI , Ayinde Hakeem , Iluyomade Adedapo
Published: April 2024

Background:
The medical management of left ventricular thrombus (LVT) is very challenging due to the risk of embolic events. The current body of evidence supports the use of DOACs (direct oral anticoagulants) as safe substitutes to vitamin K antagonists/warfarin. We aim to identify the credibility of the evidence-based claims that advocate the safety/efficacy of DOACs in comparison to warfarin therapy for LVT patients.

Methods:
We systematically explored PubMed/Medline, JSTOR, Google Scholar, and Cochrane Library to identify relevant studies published between January 2006 and April 2021. The included studies categorically compared various clinical endpoints related to the safety/efficacy of DOACs versus warfarin in LVT scenarios.

Results:
We extracted 23 studies on 172,038 adult patients who received treatment for LVT and/or cardiorenal comorbidities via DOACs or warfarin. The odds ratios for all-cause mortality (OR: 1.08, 95% CI 0.69, 1.71), arterial thrombus (OR: 0.74 [95% CI 0.03, 18.76]), bleeding complications (OR: 1.16 [95% CI 0.67, 2.02]), composite of deep venous thrombosis or pulmonary embolism (OR: 0.95 [95% CI 0.10, 8.99]), hemorrhagic stroke (OR: 0.53 [95% CI 0.02, 13.30]), composite of stroke or systemic embolism (OR: 1.08, 95% CI 0.64, 1.83), systemic embolism (OR: 0.53 [95% CI 0.02, 13.30]), and rate of thrombus resolution for DOACs (versus warfarin) (OR: 1.32 [95% CI 0.66, 2.62]) supported their safety/efficacy in LVT treatment. The subgroup analysis affirmed the safety/efficacy of betrixaban and rivaroxaban (as compared to warfarin) in minimizing the episodes of stroke/ischemic stroke and clinically relevant/intracranial hemorrhage in patients with/without cardiorenal comorbidities.

Conclusion:
We found no difference in therapeutic efficacy and safety of DOACs as compared to warfarin in managing the clinical complications of left ventricular thrombus. The findings advocate the need for prospective randomized controlled trials to validate the safe replacement of warfarin with DOACs in LVT patients.
Abstract 12758: Dissecting Heart Age Using Cardiac Magnetic Resonance Videos, Electrocardiograms, Biobanks, and Deep Learning
Authors: Le Goallec Alan , Prost Jean-Baptiste , collin sasha , Diai Samuel , Vincent Theo , Patel Chirag
Published: April 2024

Introduction:
Heart disease is the first cause of death after age 65 and, with the world population aging, its prevalence is expected to starkly increase.

Methods:
We used deep learning to build a heart age predictor on 45,000 heart magnetic resonance videos [MRI] and electrocardiograms [ECG] from the UK Biobank cohort (age range 45-81 years). (Figure 1)

Results:
We predicted age with a root mean squared error [RMSE] of 2.81±0.02 years (R-Squared=85.6±0.2%) and found that accelerated heart aging is heritable at more than 35%. MRI-based anatomical features predicted age better than ECG-based electro-physiological features (RMSE=2.89±0.02 years vs. 6.09±.0.02 years), and heart anatomical and electrical aging are weakly correlated (Pearson correlation=.249±.002). Our attention maps highlighted the aorta, the mitral valve, and the interventricular septum as key anatomical features driving heart age prediction (Figure 2). We identified genetic (e.g titin gene) and non-genetic correlates (e.g smoking) of accelerated heart aging.

Conclusions:
We built the first accurate heart age predictor, and showed that different dimensions of the heart can age at different rates. We identified genetic and non-genetic factors associated with accelerated heart aging. Our predictor can be used the assess the effect of rejuvenating therapies on cardiovascular health.
Abstract 13166: Paraoxonase-3 Regulation of Cardiotonic Steroids Mediates Renal Injury and Dysfunction in a Dahl Salt Sensitive Model of Chronic Kidney Disease
Authors: Mohammed Chrysan J , Lamichhane Sabitri , Dube Prabhatchandra , Soehnlen Sophia , Connolly Jacob , Kleinhenz Andrew , Faleel Dhilhani , Isailovic Dragan , Malhotra Deepak , Haller Steven , Kennedy David J
Published: April 2024

Background:
Paraoxonases (Pons) belong to a family of hydrolytic enzymes with 3 distinct isoforms: Pon 1, 2, and 3. While the physiologic substrates for Pons are unclear, their lactonase activity is considered central to their native physiological role. We have previously demonstrated an association between diminished Pon lactonase activity and worse clinical outcomes in volume expanded states such as chronic kidney disease (CKD). Furthermore, we have identified a novel reno-protective role for Pon3 in hypertensive renal disease. However, the underlying mechanism(s) are unknown. Cardiotonic steroids (CTS) are natriuretic hormones that are increased in CKD and promote renal inflammation and fibrosis via binding of their 17β-lactone ring to the alpha-1 subunit of the Na
+
/K
+
-ATPase (NKA-α-1). Therefore, we tested the hypothesis that reduction of Pon3 lactonase activity would lead to increased renal injury and dysfunction in a CTS induced rat model of CKD.

Methods/Results:
Experiments were performed on Dahl salt-sensitive rats (SS rats) and Pon3 knock-out rats on the Dahl salt-sensitive background (SS-
Pon3
KO). First, CTS levels in the urine of SS control and SS-
Pon3
KO rats were quantified using mass spectrometry. We found that SS-
Pon3
KO rats had 59 times greater increase in 24-hour urine CTS levels vs SS rats. Next, to examine the role of Pon3 in mediating CTS induced renal injury, ten-week-old, age-matched male SS control and SS-
Pon3
KO rats were administered the CTS telocinobufagin (TCB, 100 μg/kg/day s.q) for four weeks followed by assessment of blood pressure (tail cuff plethysmography) and renal function. We found that SS-
Pon3
KO rats following TCB administration had significantly increased 24-hour urinary protein excretion (UPE) (50.73 ± 3.59vs 25.29 ± 2.07, p<0.0001), as well as decreased FITC-Sinistrin monitored glomerular filtration rate (GFR) (0.80 ± 0.10 vs 1.16 ± 0.05, p<0.01) compared to SS control rats, despite similar degrees of hypertension.

Conclusion:
These findings suggest that Pon3 plays a critical role in regulating CTS mediated renal dysfunction in vivo.
Abstract 13745: Nicotine Delivered by Electronic Cigarette Vapor or Standard Cigarettes Adversely Affects Left Ventricular Systolic Function Measured by Cardiovascular Intrinsic Frequency in Rats
Authors: Alavi Rashid , Dai Wangde , Arechavala Rebecca J , Kleinman Michael T , Kloner Robert A , Pahlevan Niema M
Published: April 2024

Introduction:
Cardiovascular intrinsic frequency (IF) is a systems approach for the analysis of left ventricle (LV) function, arterial dynamics, and LV-arterial coupling. It was shown in a recent Framingham Heart Study (Hypertension 2021, 77(2):338-346) that higher values of the first IF (ω
1
) (derived from carotid pressure waveforms) are associated with higher risk for incident heart failure and composite CVD events. Here, we examined the effect of chronic exposure to E-cigarette and standard cigarette on ω
1
in rats.

Methods:
Adult male and female Sprague Dawley rats were exposed to: 1) Purified air (
n
=6); 2) E-cigarette vapor without nicotine (
n
=6); 3) E-cigarette vapor plus nicotine (similar amount of nicotine as the standard cigarette,
n
=6); and 4) Standard nicotine-containing cigarette smoke (
n
=9). E-cigarette was a 3rd generation type E-cigarette from VaporFi, tank model: Volt 2. Rats were placed into a nose-only exposure system. The exposures took place for 5 hours/day, 4 days/week for a total of 8 weeks. The E-liquid was a 50/50 propylene glycol/glycerin mixture with a tobacco flavor additive. After 8 weeks of exposure, the rats were anesthetized to measure the hemodynamics including invasive carotid pressure waveforms. IF parameters were computed from pressure waveforms with similar cardiac cycles.

Results:
There was no difference in ω
1
between purified air and E-cigarette vapor without nicotine; there was no significant difference in ω
1
between E-cigarette vapor with nicotine versus standard nicotine-containing cigarette smoke. ω
1
was significantly higher (P<0.005) in the nicotine-containing groups versus the non-nicotine containing groups (Fig.1).

Conclusions:
Our results suggest that nicotine delivered either by standard cigarette smoke or E-cigarette vapor adversely affects the LV systolic function, and ω
1
measured from the carotid waveform alone (that can be measured non-invasively with an iPhone app), can capture these negative effects.
Apical Ischemia Is a Universal Feature of Apical Hypertrophic Cardiomyopathy
Authors: Hughes Rebecca K. , Augusto João B. , Knott Kristopher , Davies Rhodri , Shiwani Hunain , Seraphim Andreas , Malcolmson James W. , Khoury Shafik , Joy George , Mohiddin Saidi , Lopes Luis R. , McKenna William J. , Kellman Peter , Xue Hui , Tome Maite , Sharma Sanjay , Captur Gabriella , Moon James C.
Published: April 2024

Background:

Apical hypertrophic cardiomyopathy (ApHCM) accounts for ≈10% of hypertrophic cardiomyopathy cases and is characterized by apical hypertrophy, apical cavity obliteration, and tall ECG R waves with ischemic-looking deep T-wave inversion. These may be present even with <15 mm apical hypertrophy (relative ApHCM). Microvascular dysfunction is well described in hypertrophic cardiomyopathy. We hypothesized that apical perfusion defects would be common in ApHCM.

Methods:

A 2-center study using cardiovascular magnetic resonance short- and long-axis quantitative adenosine vasodilator stress perfusion mapping. One hundred patients with ApHCM (68 overt hypertrophy [≥15 mm] and 32 relative ApHCM) were compared with 50 patients with asymmetrical septal hypertrophy hypertrophic cardiomyopathy and 40 healthy volunteer controls. Perfusion was assessed visually and quantitatively as myocardial blood flow and myocardial perfusion reserve.

Results:

Apical perfusion defects were present in all overt ApHCM patients (100%), all relative ApHCM patients (100%), 36% of asymmetrical septal hypertrophy hypertrophic cardiomyopathy, and 0% of healthy volunteers (
P
<0.001). In 10% of patients with ApHCM, perfusion defects were sufficiently apical that conventional short-axis views missed them. In 29%, stress myocardial blood flow fell below rest values. Stress myocardial blood flow was most impaired subendocardially, with greater hypertrophy or scar, and with apical aneurysms. Impaired apical myocardial blood flow was most strongly predicted by thicker apical segments (β-coefficient, −0.031 mL/g per min [CI, −0.06 to −0.01];
P
=0.013), higher ejection fraction (−0.025 mL/g per min [CI, −0.04 to −0.01];
P
<0.005), and ECG maximum R-wave height (−0.023 mL/g per min [CI, −0.04 to −0.01];
P
<0.005).

Conclusions:

Apical perfusion defects are universally present in ApHCM at all stages. Its ubiquitous presence along with characteristic ECG suggests ischemia may play a disease-defining role in ApHCM.
The auditory P2 is influenced by pitch changes but not pitch strength and consists of two separate subcomponents
Authors: Steinmetzger Kurt , Rupp André
Published: April 2024

The P2 component of the auditory evoked potential has previously been shown to depend on the acoustic stimulus properties and prior exposure to the materials. Here, we show that it is also affected by acoustic changes, as P2 amplitudes were strongly enhanced in response to voice pitch changes with a stepwise pattern compared to dynamic pitch changes typical for natural speech, and also reflected the magnitude of these pitch changes. Furthermore, it is demonstrated that neither the P2 nor any other component is affected by the harmonicity of the materials. Despite no prior exposure and a weaker pitch, artificially created inharmonic versions of the materials elicited similar activity throughout the auditory cortex. This suggests that so-called harmonic template neurons observed in animal studies are either absent or do not exist in sufficient number in the human auditory cortex to detect their activity extracranially. Crucially, morphology as well as scalp maps and source reconstructions of the EEG data showed that the P2 appears to consist of two separate subcomponents. While the “P2a” was localised to the auditory cortex, the subsequent “P2b” included generators spread across the auditory cortex and association areas. The two subcomponents thus likely reflect processing at different stages of the auditory pathway.
A thin line between conflict and reaction time effects on EEG and fMRI brain signals
Authors: Beldzik Ewa , Ullsperger Markus
Published: April 2024

The last two decades of electrophysiological and neuroimaging research converged that the activity in the medial frontal cortex plays a pivotal role in cognitive control processes. Notably, the midfrontal theta (MFT) oscillatory EEG power as well as activity in the anterior midcingulate cortex (aMCC) or pre-supplementary motor area (preSMA) were consistently proclaimed as markers of conflict processing. However, these brain signals are strongly correlated with response time (RT) variability in various non-conflict tasks, which overshadows the true nature of their involvement. Our previous study (Beldzik et al., 2022) successfully identified these brain signals during a simultaneous EEG-fMRI experiment implementing Stroop and Simon tasks. Based on the assumption that overcoming the habitual prepotent response during high interference trials requires additional neural resources beyond simple decision variable represented in RTs, here we aim to verify if these markers exhibit a congruency effect beyond RT variations. Furthermore, we explored if these brain signals represent either proactive or reactive cognitive control mechanisms by investigating two widely known behavioral phenomena observed in conflict tasks: proportion congruency and congruency sequence effects. The results revealed partially null findings for MFT activity, yet a distinct cognitive control specialization between aMCC and preSMA. Our study provides novel evidence that the former is involved in proactive control mechanisms, possibly contingency learning, whereas the latter reflects reactive control mechanisms by exhibiting a strong congruency effect regardless of RT variation and responding to adaptive behavior.