Abstract 4146347: Oxidative Stress Lipids Associate with Mood Disturbance Symptoms and Quality of Life in Acute Ischemic Stroke Patients

Circulation, Volume 150, Issue Suppl_1, Page A4146347-A4146347, November 12, 2024. Background:Acute ischemic stroke (AIS) is a leading cause of mortality and disability globally, disproportionately affecting Black and Latinx populations who experience increased morbidity and mortality compared to their white counterparts. At one month, roughly 50% of AIS survivors experience mood disturbances (e.g., anger, irritability, and aggression) and exhibit a lower health-related quality of life (HRQOL) compared to pre-AIS levels. Downstream biomarkers of mitochondrial dysfunction such as oxidative stress may be important pathophysiological mechanisms underlying mood disturbance symptoms, stroke severity, and long-term functional recovery.Purpose:To examine associations among early and late peripheral plasma lipid levels, mood disturbance symptoms (e.g., anger, irritability), and HRQOL outcome over 3 months (baseline/study day 5, and months 1, 3) in persons following AIS.Methods:The pilot study is a non-probability, convenience sample of adult subjects ( > 18 years of age) with a diagnosis of AIS. Lipidomics analysis was performed using liquid chromatography-mass spectrometry (LC-MS) of untargeted lipids. The Agilent 6545 LC/Q-TOF platform was used to determine the absolute concentration of lipid species from peripheral plasma samples collected days 1, 3, 5 and months 1 and 3 post-AIS. General linear mixed models were used to test the predictive association of lipidomic biomarker mean value of peripheral plasma lipid levels and symptoms and outcomes over time (baseline and months 1 and 3).Results:We analyzed 82 subjects (age = 64 ± 12.1, 52% male, 78% Black, and 94% with hypertension). Elevated oxidative stress biomarkers (e.g., lipoxygenases, arachidonic acid, glycosylphosphatidylinositol) were associated with higher severity of anger and irritability symptoms, and a poorer HRQOL from baseline to 1- and 3-months post-AIS (p=0.04).Conclusion:An untargeted LC-MS lipidomics approach was used to identify lipids following AIS. Because oxidative stress plays a key regulatory role in complex downstream cellular function, these findings may be of great significance in understanding AIS pathophysiology that has the potential to inform personalized preventive strategies.

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Abstract 4142987: Cardiac TRPM7 kinase plays a key role on diabetic heart failure with preserved ejection fraction

Circulation, Volume 150, Issue Suppl_1, Page A4142987-A4142987, November 12, 2024. Introduction:Hypomagnesemia (HypoMg) and subsequent oxidative stress cause diabetic cardiac diastolic dysfunction (DD) and heart failure with preserved ejection fraction (HFpEF). A Mg2+transporter with both channel and kinase function, the transient receptor potential cation channel subfamily M 7 (TRPM7), is upregulated in HypoMg. Inhibition of TRPM7 kinase prevents HypoMg-mediated oxidative stress in the brain.Aims:We investigated the role of TRPM7 kinase in cardiomyocyte mitochondrial regulation and DD.Methods:Wild type (WT) C57BL/6J mice and transgenic mice with a global K1646R mutation in the TRPM7 kinase domain, TRPM7K1646R(without kinase function) were fed with either a normal diet (control, 2000 mg/kg Mg2+), high fat diet (HFD, 60% kcal from fat), or a low Mg2+diet (HypoMg, 15-30 mg/kg Mg2+) starting from 10 weeks old. HFD lasted for 23-25 weeks. HypoMg diet lasted for 6 weeks. Mouse ventricles, cardiomyocytes, and mitochondria and human cardiac cell line, RL-14, were used for analysis.Results:Diabetic mice on HFD had HypoMg and elevated TRPM7 protein levels in heart. DM-associated DD was prevented by TRPM7K1646R. In HypoMg mouse ventricles, TRPM7 mRNA and protein levels were also increased. HypoMg-induced DD (increased E/e’, decreased resting sarcomere length, and increased S-glutathionylated cardiac myosin binding protein C) and mitochondrial dysfunction (increased mitoROS, depolarized mitochondrial membrane potential, and decreased ATP, mitochondrial Mg2+and complex I/II activities) were prevented by TRPM7K1646R. TRPM7 kinase regulated the overexpression of a Src kinase family member Fgr in mitochondria of HypoMg mouse ventricles, which co-localized with complex II, regulated complex II activity, and led to increased mitoROS.Conclusion:TRPM7 mediated mitochondrial dysfunction and cardiac DD in HypoMg. TRPM7 kinase enhanced Fgr expression in mitochondria, with subsequent complex II dysfunction and mitoROS overproduction. Inhibition of TRPM7 kinase function represents a potential novel therapeutic strategy to treat diabetic HFpEF.

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Abstract 4142028: An Intensive Lifestyle Intervention Improves Cardiovascular Health Outcomes in Patients with Type-2 Diabetes

Circulation, Volume 150, Issue Suppl_1, Page A4142028-A4142028, November 12, 2024. Background:Type 2 diabetes (T2D) is associated with an elevated risk of cardiovascular (CV) complications, including hypertension, dyslipidemia, obesity, and inflammation. Addressing CV risk factors is crucial for reducing morbidity and mortality in affected individuals. Integrated lifestyle interventions have emerged as promising strategies for managing T2D and its associated CV risks, emphasizing the importance of dietary modifications, physical activity, and stress management in improving health outcomesResearch AimThis study evaluated the impact of an intensive lifestyle intervention (ILI) on both traditional and non-traditional cardiovascular risk factors in patients with type 2 diabetes (T2D)Methods:This retrospective study of 6028 patients diagnosed with T2D (≥18 years), who enrollled in a one-year online ILI program at Freedom from Diabetes Clinic, Pune, India between January 2021 and December 2022. The intervention included a personalized plant-based diet, exercise regimen, stress management, and medical support. Baseline and endline data on CV risk factors, socio-demographics, anthropometry, and medical history were extracted. The primary outcome was an improvement in the CV profile.Results:The mean age of the study population was 51.7±10.4 years (64% male) with a mean diabetes duration of 10.9±7.6 years. At baseline, the majority (67.7%) were on glucose-lowering medication; 39.9% and 51.9% were on anti-hypertensives and statins, respectively. Despite being on medication, 70.2% had poor glycemic control (HbA1c >7%); while dyslipidemia (triglycerides ≥150 mg/dl), obesity (≥25 kg/m2), and hypertension (≥140/90 mmHg) affected 38.8%, 56.3%, and 18.7% of the patients, respectively. Following intervention, there was significant improvement in HbA1c (-17.1%) and weight (-5.3%) (p

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Abstract 4139928: Ketone Body Metabolism Exerts an Anti-hypertrophic Effect on Cardiomyocytes by Alleviating Fatty Acid Overload and Increasing Glucose Utilization.

Circulation, Volume 150, Issue Suppl_1, Page A4139928-A4139928, November 12, 2024. Background:Ketone body metabolism, known for its multifaceted effects, is gaining attention as a potential therapeutic target for cardiovascular diseases. However, the impact of ketone bodies on cardiac hypertrophy and Heart Failure with Preserved Ejection Fraction (HFpEF) remains unclear.Research Questions:To elucidate the effects of ketone bodies on cardiac hypertrophy.The aim of the present research is to investigate the impact of ketone bodies on cardiac hypertrophy induced by metabolic abnormalities using organ-specific ketone body synthesis-deficient mice.Methods:Obesity and hypertension were induced by a high-fat diet combined with NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) (Combined Stress), and the resultant cardiac hypertrophy and ketone body synthesis were evaluated. Subsequently, organ-specific knockout mice of HMG-CoA synthase 2 (Hmgcs2), a rate-limiting enzyme in ketone body synthesis, were subjected to Combined Stress to assess the impact on cardiac hypertrophy. To conduct a metabolism-focused analysis, cell type-specific nuclei were isolated and subjected to RNA sequencing (RNA-seq) and comprehensive metabolomics analysis. To evaluate the direct effects of ketone bodies, H9C2 cells, rat cardiac cells ,were treated with β-hydroxybutyrate, followed by analysis of oxygen consumption and metabolomics.Results:Combined Stress resulted in increased myocardial cross-sectional area and enhanced ketone body synthesis in the liver and heart. Hepatocyte-specific Hmgcs2 knockout mice (Hmgcs2ΔHep) subjected to Combined Stress exhibited exacerbated myocardial hypertrophy (cardiomyocyte cell size;Hmgcs2flox: 322.8 ± 88.3 μm2:Hmgcs2ΔHep: 444.0 ± 118.5 μm2; p < 0.0001). RNA-seq analysis revealed that the upregulation of glycolytic genes induced by Combined Stress did not occur inHmgcs2ΔHepmice, and a metabolic phenotype favoring fatty acid oxidation persisted. In the liver, hepatocyte destruction and increased serum fatty acid levels were observed. Additionally, H9C2 cells treated with β-hydroxybutyrate showed decreased fatty acid utilization and increased glucose utilization.Conclusion:In cardiac hypertrophy induced by obesity and hypertension, ketone body synthesis mitigates fatty acid overload and promotes glucose utilization, thereby exerting an anti-hypertrophic effect.

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Abstract 4142998: Optimizing Transcatheter Aortic Valve Design to Mitigate Subclinical Leaflet Thrombosis

Circulation, Volume 150, Issue Suppl_1, Page A4142998-A4142998, November 12, 2024. Introduction:Subclinical leaflet thrombosis is an increasingly recognized complication in patients undergoing transcatheter aortic valve replacement (TAVR). Patients with hypoattenuated leaflet thickening (HALT) and reduced leaflet motion (RELM) have a higher incidence of strokes and transient ischemic attacks. Early clinical data suggested that HALT is more common in supra-annular than intra-annular transcatheter aortic valves (TAVs). It was postulated that intra-annular TAVs have a larger neo-sinus volume and are potentially at a higher risk of blood flow stagnation in the neo-sinus region than supra-annular devices. However, recent clinical data obtained from the Evolut Low-Risk trial and the PARTNER 3 Cardiac CT sub-study showed that the incidence of HALT was comparable between supra-annular Evolut R (30.9%) and intra-annular SAPIEN 3 (28%) devices at one year.Hypothesis:We hypothesized that TAV leaflet design plays a vital role in the initiation and growth of leaflet thrombosis.Aim:The study aimed to optimize the leaflet and frame geometry of TAVs to mitigate the risk of subclinical leaflet thrombosis using an interactive parametric design platform that streamlines the engineering design process.Methods:We developed an automated computational framework to optimize the design of TAV leaflets in ANSYS Workbench, aiming to minimize (i) blood stasis on the surface of the TAV leaflets and (ii) the peak stress experienced by the tissue. Seven design variables were defined to modify the leaflet geometry and valve position (Figure 1).Results:The design platform revealed a complex response of the design variables, underscoring the importance of numerical optimization to obtain an optimal valve geometry. A considerable reduction in the blood stasis and maximum in-plane principal stress (31%) was observed in comparison to commercially available TAVs.Conclusions:The simulation results revealed that the leaflet geometry plays a vital role in the degree of blood stasis on the surface of the TAV leaflets and the stress experienced by the tissue. The optimized TAV design could reduce the risk of subclinical leaflet thrombosis in patients undergoing TAVR.

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Abstract 4146225: Stress Perfusion Cardiac Magnetic Resonance Imaging for Pediatric Patients with Repaired Transposition of the Great Arteries

Circulation, Volume 150, Issue Suppl_1, Page A4146225-A4146225, November 12, 2024. Introduction:Patients who underwent arterial switch operation (ASO) for d-transposition of the great arteries (TGA) are at increased risk for early myocardial ischemia. Stress perfusion cardiac MR (SPCMR) is used as a non-invasive tool for risk stratification but interpretation is often challenging.Hypothesis:There is significant interobserver variability in SPCMR image interpretation in patients with repaired TGA.Aims:1. Determine incidence and severity of adverse effects of stress agents.2. Evaluate incidence of positive SPCMR.3. Assess agreement amongst reviewers in image interpretation.Methods:Patients with repaired TGA with SPCMR imaging from 2013 to 2024 were reviewed. Three patients with previous coronary intervention and one with severe chest pain after adenosine, unable to complete SPCMR, were excluded. 61 studies were performed in 56 patients. Images were independently reviewed by two investigators blinded to initial interpretation and clinical outcome. Perfusion defects were displayed on a circumferential polar plot using standard LV segmentation.Results:Median (IQR) age was 15 (11-17) years, weight 55 (36-68) kg, and BSA 1.6 (1.2-1.8) m2. Max heart rate was 110 (100-125) and systolic BP 127 (116-138). Eleven (20%) patients had cardiac symptoms, chest pain in 9 (16%), syncope in 1 (2%), pallor and distress in 1 (2%) infant. Adverse effects from SPCMR in 8/52 (15%) adenosine, 2/4 (50%) dobutamine, and 0/6 (0%) regadenoson were minor and resolved on stress completion. Six (10%) studies were initially interpreted as suspicious (n=5) or definitive (n=1) perfusion defect (Figure). No LGE was detected. Original interpretation did not match blinded reviews for 6 cases (Figure). Blinded reviewers agreed on 3 negative cases but interpretation differed in the other 3 cases (Figure).Conclusions:SPCMR is safe and feasible. Significant interobserver variability highlights the challenges in qualitative SPCMR interpretation for TGA. Quantitative perfusion may reduce interobserver variability. Larger multicenter studies would be helpful in further elucidating the risk profile of patient characteristics and coronary artery arrangements to determine whether routine use of SPCMR is warranted for TGA patients.

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Abstract 4142869: Heritable heart failure traits in mice undergoing early life stress

Circulation, Volume 150, Issue Suppl_1, Page A4142869-A4142869, November 12, 2024. Introduction:Adverse childhood experiences, also known as early life stress (ELS), are associated with increased risk of cardiovascular disease in later life, yet the underlying mechanisms remain elusive. Recent evidence indicates that parental life experiences can be transmitted to the offspring.Aim:To investigate the effects of ELS on cardiac structure and function in exposed parents and in their offspring, across 3 generations.Methods:We used ELS mouse model based on unpredictable separation of mouse pups (F1) from their mother (F0) each day for 3 hours from postnatal day 1 (PND1) to PND14 combined with dams exposure to an additional unpredictable stressor (forced swim in 18°C water for 5 minutes or 20-minute physical restraint in a tube) during separation. Control litters were raised normally. Echocardiography was performed at 6, 12 and 18 months in exposed animals (F0), their unexposed offspring (F1) and grand-offspring (F2). Both male and female mice were studied. Heart weight/tibia length was used to assess cardiac mass while Masson’s Trichrome was employed to detect fibrosis. Lung congestion was assessed as lung wet/dry weight ratio. Single-cell RNA sequencing (scRNAseq) was performed in MSUS and control hearts. A 6-week environmental enrichment (EE) program (cages containing running wheels, maze) was employed to test the possible rescue of ELS effects in adult males and their offspring.Results:F1 MSUS mice displayed increased LV mass, impaired diastolic function (assessed by conventional and tissue Doppler analysis) myocardial fibrosis and lung congestion. Time-dependent worsening of cardiac performance was observed from 6 to 18 months, both in males and females. ScRNAseq unveiled dysregulation of transcriptional programs underlying inflammation and lipotoxicity in the cardiomyocyte and endothelial cell clusters. MSUS offsprings did not show changes of cardiac function at 6 months, however diastolic dysfunction and lung congestion were observed at 12 and 18 months. A similar impairment of cardiac function was observed in the MSUS grandoffspring (F3). Of interest, 6-week exposure to an environmental enrichment protocol was able to improve LV mass, diastolic function and lung congestion in 12 months-old MSUS mice.Conclusions:ELS induces a transgenerational transmission of cardiac phenotypic alterations which can be rescued by EE. Our results shed light on the potential role of ELS on heart failure development and potential mitigation strategies.

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Abstract 4125691: A machine learning approach to examining the associations of minority stressors and physical activity among sexual and gender minority adults

Circulation, Volume 150, Issue Suppl_1, Page A4125691-A4125691, November 12, 2024. Introduction:Physical activity (PA) is an important modifiable factor for cardiovascular disease (CVD). Sexual and gender minority (SGM; e.g., lesbian/gay, bisexual, transgender) adults face higher risks of inadequate PA and CVD due to increased exposure to minority stressors, such as experienced and anticipated discrimination, which may influence SGM adults’ willingness to engage in PA. To our knowledge, researchers have not investigated the impact of minority stressors on objectively-measured PA among SGM adults.Goal:Using k-means clustering, we sought to identify whether clusters characterized by greater exposure to minority stressors were associated with lower moderate and vigorous PA (MVPA) and higher sedentary behavior among SGM adults.Methods:This daily diary study included an online sample of SGM adults living in the United States. Participants completed daily surveys about personally experienced discrimination and anticipated discrimination (i.e., expectation of experiencing discrimination) and wore wrist accelerometers for 28 days to objectively measure PA. We used k-means clustering to identify clusters based on reports of experienced and anticipated discrimination. We first determined the optimal number of clusters using established partition criteria. Next, we ran linear regression models (adjusted for demographic factors) to examine the associations of minority stress clusters with MVPA and sedentary time per week.Results:Among 42 SGM adults (mean age 27.0±7.7 years) with 1133 person-days of accelerometry data (~3% missing data), we identified four minority stress clusters: low anticipated/low experienced (LALE; reference group); low anticipated/high experienced (LAHE); high anticipated/low experienced (HALE); and high anticipated/high experienced discrimination (HAHE). Participants in the HALE cluster (n=12) engaged in 202 fewer minutes of MVPA than those in the LALE cluster (n=7). Participants in the LAHE cluster (n=10) had 123 fewer minutes of vigorous PA than those in the LALE cluster. No differences were identified for sedentary time.Conclusions:This is the first study to examine the association of minority stressors with objective PA among SGM adults. Participants in the HALE and LAHE clusters engaged in significantly lower PA than those with low levels of both experienced and anticipated discrimination. Findings underscore the importance of assessing minority stressors and the need for interventions to improve PA among SGM adults.

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Abstract 4129729: Relationship Between Inflammatory Biomarkers and Quality of Life in Black Adults Living with Heart Failure: A Pilot Study

Circulation, Volume 150, Issue Suppl_1, Page A4129729-A4129729, November 12, 2024. Introduction:Heart failure (HF) impacts quality of life considerably, with inflammatory biomarkers potentially playing a significant role in this relationship. The purpose of this study is to examine the relationship between NYHA Class, inflammatory biomarkers, and quality of life in Black adults living with HF.Methods:Black adults living with HF (N=41) were enrolled in this study. NYHA Class was extracted from the medical record. Health-related quality of life was measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ), a 23-item questionnaire that quantifies physical function, symptoms, social function, and health-related quality of life in HF. Scores are transformed to a range of 0-100, with higher scores reflecting better health status. One-way ANOVA and correlation analyses were used to assess associations between NYHA class, inflammatory biomarkers (XO activity, IL-1β, IL-15, and CCL-19), and KCCQ scores.Results:Participants were 57±11 years of age and 66% female, with mean LVEF 33±14%. NYHA Class ranged from I (20%) to IV (12%), with the majority of participants in Class II (34%) and III (22%). Mean KCCQ Clinical Summary Score was 85± 21. NYHA Class I had significantly lower scores on the KCCQ Clinical Summary Score compared to Class III and IV (p < .001, η2= 0.54), KCCQ Physical Limitation compared to Class II, III, and IV (p < .001, η2= 0.53), and KCCQ Symptom Frequency compared to Class IV (p = .001, η2= 0.39). The KCCQ Clinical Summary Score was negatively associated with XO activity (r = -0.440, p = .046), IL-1β (r = -0.407, p = .043), IL-15 (r = -0.427, p = .033), and CCL-19 (r = -0.559, p = .004). Similar negative associations were observed for the KCCQ subscales.Conclusion:The negative association between XO activity and health-related quality of life (KCCQ) in individuals with HF highlights the potential impact of oxidative stress on these patients' subjective well-being and functional status. Understanding this relationship could underscore the importance of mitigating oxidative stress pathways to improve the overall quality of life and symptom burden experienced by individuals with HF. The KCCQ and subscales were also negatively associated with markers of inflammation, highlighting the potential impact of systemic inflammatory processes on subjective well-being and functional status in persons with HF. Targeting inflammatory pathways may improve quality of life and mitigate the burden of symptoms in HF.

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Abstract 4136181: Automated Personalized Modulation of the Sympathetic “fight-or-flight” Reflex In Vivo Using Implantable Microdevices for Enhancing Neurocardiac Function and Reducing Mortality Risk.

Circulation, Volume 150, Issue Suppl_1, Page A4136181-A4136181, November 12, 2024. Background:The sympathetic nervous system (SNS) is a critical regulator of cardiovascular function. Whereas acute SNS activation elicits positive inotropy and confers survival advantage, persistent SNS hyperactivity is maladaptive and can lead to arrhythmias, cardiac arrest and heart failure.Hypothesis:Automated optogenetic modulation of the sympathetic stress responsein vivoenhances neurocardiac function while avoiding sympathetic hyperactivity-mediated pathological effects.Methods:In normal guinea pigs, we virally transduced excitatory and/or inhibitory channelrhodopsins to the stellate ganglia (SG), the primary sympathetic input to the heart. We studiedin situeffects of graded activation of SG opsins (e.g., phasic vs tonic) on cardiac function (e.g., ECG, heart rate) with and without perfusing agents (e.g., β-blockers, antioxidants).In vivostudies used novel implanted µLED devices for wireless body signal streaming (e.g., ECG) and neurophotonic SG opsin modulation closed-loop to dynamic analyses of physiological demand versus ECG-based cardiac risk prediction.Results:Compared to baseline heart rate (218±16 bpm), pulsed activation of inhibitory opsins reduced heart rate by ~25% (156±12; delta=67±14 bpm; p

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Abstract 4148019: Shear Stress Affects Human Aortic Endothelial Heparan Sulfate Expression Response to Inflammatory Stimulus

Circulation, Volume 150, Issue Suppl_1, Page A4148019-A4148019, November 12, 2024. Background:Heparan sulfate (HS) proteoglycans act as mechanosensors on endothelial cells (ECs), regulating EC morphology and function. HS expression is affected by culture under static or dynamic conditions. HS response to inflammatory stimulus under both conditions is not well characterized. This study investigated HS expression on human aortic ECs (HAECs) under static and arterial flow conditions.Hypothesis:Inflammation modeled by TNFa significantly decreases HS epitope on HAECs under both static and arterial flow conditions.Aims:To establish the effect of TNFa on HS expression in HAECs.Methods:Passages 4 through 8 HAECs (ATCC) were cultured to confluence in endothelial growth medium (Vasculife) in Ibitreat µ-Slide 8 well high chambered coverslip slides or Ibitreat µ-Slide VI 0.4 flow channel slides. Cells were treated with TNFa at 100 ng/mL for 3 hours under static conditions or conditioned with 10 dyn/ cm2 of shear stress for 24 hours and then treated with TNFa at the same concentration added to the circulating media for 3 hours. HAECs were fixed in 2% paraformaldehyde/ 0.1% glutaraldehyde for 30 minutes followed by blocking with 2% goat serum for 30 minutes, both at room temperature. Primary antibody to the 10E4 HS epitope was incubated at 4°C overnight (1:100; 10E4 epitope, AMS Biotechnology, USA) followed by incubation in Alexa Fluor 488 goat anti-mouse secondary antibody (1:300, Molecular Probes, USA) for 1 hour at room temperature. HAECs nuclei were stained using 4′,6-diamidino-2-phenylindole and immersed in phosphate buffered saline for confocal imaging using a laser scanning microscope (Zeiss, LSM 880, 20X).Results:TNFa significantly (p < 0.05) increased HS expression in HAEC monolayers treated under static conditions compared to untreated control and heparinase III treated HAECs (Figure 1A). HAEC monolayers conditioned under arterial shear stress expressed significantly (p < 0.05, ANOVA with Tukey’s post-hoc) higher HS levels compared to baseline static controls; however, flow conditioned HAECs did not show any difference in HS expression under untreated compared to TNFa conditions (Figure 1B).Conclusion:These data indicate that fluid shear stress may program endothelial cells to significantly alter their HS expression and response to inflammatory stimuli.

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Abstract 4145408: The Unexpected Heart Stopper: A Case of Ketamine-Induced Stress Cardiomyopathy Requiring Mechanical Circulatory Support

Circulation, Volume 150, Issue Suppl_1, Page A4145408-A4145408, November 12, 2024. Background:Stress cardiomyopathy (SCM) is rarely triggered by ketamine and seldom leads to cardiogenic shock. Ketamine-induced catecholaminergic surge can lead to myocardial stunning with transient ischemia and subsequent reversible heart failure. Mechanical circulatory support can be successfully leveraged in SCM-associated cardiogenic shock while awaiting myocardial recovery.Case Presentation:A 28-year-old female with chronic pain was admitted for failure to thrive secondary to opioid-induced gastroparesis. The patient was weaned off opiates while on ketamine over 4 days. After halting ketamine, the patient had a cardiac arrest with eventual return of spontaneous circulation. After being extubated, she developed chest pain, hypotension, and ventricular tachycardia with anterolateral ST elevations, troponin leak, and lactic acidosis. TTE revealed an EF

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Abstract 4146330: Circular-RNA telomerase reverses endothelial senescence

Circulation, Volume 150, Issue Suppl_1, Page A4146330-A4146330, November 12, 2024. Background:Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutation in LaminA (progerin), and is characterized by accelerated aging and death from coronary or carotid disease in the mid-teens. We have shown that vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) derived from HGPS children manifest many of the hallmarks of aging including telomere erosion, reduced proliferation, impaired function, DNA damage and senescence markers, altered cellular and nuclear morphology, and an aberrant transcriptional profile. These hallmarks of aging are substantially reversed by treatment with telomerase (hTERT) linear RNA,with greater benefit in HGPS cells than the current therapy, lonafarnib. However, linear RNA has a short half-life, which necessitates frequent administration. By contrast, circular (circ) RNA is more stable than linear RNA, and with an internal ribosome entry site can be translated into protein. We hypothesized the hTERT circRNA would provide for longer duration of telomerase expression, and would have a greater benefit for HGPS ECs.HGPS ECs were treated with hTERT linear or circ RNAs. A single treatment with 1 µg/ml hTERT circRNA reversed multiple stigmata of senescence. However, at day 28 post treatment, the benefit of hTERT circRNA exceeded that of hTERT linear RNA in all measured variables. hTERT circRNA provided for greater recovery of telomere length as determined by quantitative fluorescence in situ hybridization; induced a three-fold greater reduction in beta-gal positive cells and morphologically aberrant nuclei. In HGPS ECs, hTERT circRNA provided for a 2-3 fold greater reduction of senescentfactors, inflammatory cytokines and DNA damage signals, including Progerin, p16, p21, IL-1B, IL-6, IL-8 MCP-1 and gH2A.X. In addition, hTERT circRNA to a greater degree restored NO production, promoted cell proliferation, enhanced angiogenesis and improved LDL uptake. Importantly, mitochondrial functions, as evaluated by the oxidative stress marker (MitoSOX) and mitochondrial membrane potential marker (JC-1 staining), were restored more completely by hTERT circRNA.Conclusion:hTERT circRNA is more effective than hTERT linear RNA in rejuvenating senescent ECs, possibly because of its longer half-life. The novel hTERT circRNA is a promising therapy for HGPS and other disorders associated with accelerated vascular aging.

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Abstract 4142989: Myocardial Perfusion Reserve Index in Pediatric Heart Transplant Recipients

Circulation, Volume 150, Issue Suppl_1, Page A4142989-A4142989, November 12, 2024. Background:Cardiovascular magnetic resonance (CMR) has an emerging role in graft surveillance for pediatric heart transplant recipients (PHTR). Transplanted grafts are susceptible to cardiac allograft vasculopathy, manifested as macrovascular narrowing on angiography, as well as micro-vessel disease. By CMR, myocardial perfusion abnormalities can be evaluated semi-quantitatively, by calculation of a myocardial perfusion reserve index (MPRI). However, normal MPRI values have not been well established in PHTR and prior investigation of associations between MPRI and graft pathology remain limited.Research Aims:The goals of this study were to describe the MPRI findings in a large cohort of PHTR and to evaluate clinical associations with low MPRI.Methods:We performed a retrospective chart review of consecutive, stress CMR studies at a single center from 2015-2024. Follow-up studies were excluded. Biventricular volume and function analyses were performed. A total dose of 0.15mg/kg gadobutrol was administered for rest and stress imaging. Regadenoson was the pharmacologic stressor at dose of 6-10mcg/kg, up to max 400mcg. Time signal intensity curves were obtained from perfusion datasets at stress and rest at the base, mid-ventricle, and apex. Segmental MPRI was calculated as a ratio of the maximal upslopes of the curves at stress versus rest. Global MPRI was computed as a mean of all segments.Results:128 PHTR were included. Mean age was 12.5±5.3y, with 5.9±3.8y since transplant. A clinical concern prompted CMR in 18% of studies; in 82% the indication was routine surveillance. History of CAV was present in 6% and moderate or severe rejection in 22%. In 11 studies, images were inadequate for MPRI analysis. In the 117 studies included for analysis, global MPRI was normally distributed with mean 1.38±5.3. Mean MPRI observed at the mid-ventricle (1.49±0.46) was higher than at the base (1.32±0.32) and apex (1.33±0.39), (p

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Abstract 4142845: Efficacy of full petticoat TEVAR in Stanford type B aortic dissection with patent false lumen and computational fluid dynamics analysis of the remodeling mechanism

Circulation, Volume 150, Issue Suppl_1, Page A4142845-A4142845, November 12, 2024. Introduction:Uncomplicated Stanford type B acute aortic dissection is traditionally managed with strict blood pressure control. However, many patients who survive the acute phase develop dissecting aortic aneurysms owing to false lumen expansion in the chronic phase.Objectives:This study investigated treatment strategies for Stanford type B aortic dissection, specifically comparing the outcomes of full provisional extension to induce complete attachment (PETTICOAT) thoracic endovascular aortic repair (TEVAR) with those of simple entry closure using TEVAR. This study aimed to elucidate the long-term results of full PETTICOAT TEVAR and the mechanisms underlying false lumen expansion or suppression through computational fluid dynamics analysis.Methods:This retrospective study included 22 patients diagnosed with Stanford type B aortic dissection: 12 in the full PETTICOAT group and 10 in the entry closure group. Computed tomography images were analyzed at various time points till four years postoperatively by measuring the aortic, true lumen, and false lumen diameters at four levels. Statistical analyses were performed using Welch’s t-test, and statistical significance was defined as p < 0.05. Additionally, blood flow analysis was performed for one case from each group. We aimed to approximate solutions from the fluid equations, visualize blood flow, and compare hemodynamic parameters, namely wall shear stress and oscillatory shear index.Results:In the fourth postoperative year, there was a significant difference in aortic diameter (p = 0.012) and false lumen diameter (p = 0.001) at level 3 (diaphragm level of the descending aorta), and the full PETTICOAT group showed smaller values indicative of favorable remodeling. Blood flow analysis revealed elevated oscillatory shear index values in the false lumens of the entry closure group, suggesting a correlation with false lumen expansion.Conclusions:Full PETTICOAT TEVAR demonstrated positive long-term outcomes by reducing the false lumen and preventing aortic enlargement. This study provides insights into the underlying hemodynamic mechanisms, emphasizing the potential of computational fluid dynamics analysis in understanding aortic dissection treatment strategies.

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Abstract 4139423: Glycemic Changes After Peer Group Exergaming and Step Goal Activities Among Adolescents With Type 1 Diabetes

Circulation, Volume 150, Issue Suppl_1, Page A4139423-A4139423, November 12, 2024. Adolescents with type 1 diabetes (T1D) experience both psychosocial and self-management barriers to physical activity (PA). We previously reported on a peer support intervention with group exergaming and step-counting goals for adolescents with T1D. The intervention yielded high participation, motivation, perceived group cohesion, and participant satisfaction. The purpose of the present sub-study was to assess 24hr continuous glucose monitoring (CGM) changes following the biweekly 20-40min group exergaming sessions (Nintendo Ring Fit Adventure) across the 6-week intervention, adjusted for other daily PA tracked by smartwatch (Fitbit Inspire 2). Participants (n=15) were mean age 15.6 [SE=0.4] years, 7 non-Hispanic white, 6 female, 1 non-binary, mean A1c 8.9%±0.6%. They provided 75.3% of possible 24hr CGM readings (n=12 Dexcom G6, n=3 Abbott Libre 2) and 70.5% of possible 24hr Fitbit readings, thus 1,008 person-hours with CGM and Fitbit. In a 2-level linear model (i.e., within-person biometrics from CGM and Fitbit, after adjustment for between-person HbA1c and age), hours ≤24hr after exergaming sessions – compared to hours >24hr after them – had lower average glucose (185mg/dL [95% CI 173,196] vs 192mg/dL [177,214], t=-2.66,P

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